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BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Background: Immunosuppressive therapy is the standard management of adults with aplastic anaemia. Antithymocyte globulin is used as first-line treatment of patients not eligible for bone marrow transplantation. This being a rare disease, available evidence in India is scarce. This study aimed to present experience in treating adult aplastic anaemia patients by immunosuppressive therapy using antithymocyte globulin-equine (Thymogam) in two tertiary care centres of northeast India. Methods: This case series was conducted at the Health city hospital, Guwahati, and Excel Care Hospital, Guwahati from 2018 to 2020. Eighteen adult aplastic anaemia patients who were treated by immunosuppressive therapy with antithymocyte globulin-equine (Thymogam) and followed up for two years were included. Treatment response and relapse are described. Results: All the 18 patients, (14 severe, four very severe) were uniformly treated with immunosuppressive therapy (Thymogam 40 mg/kg/d for four days with oral Cyclosporine from Day-1). Cyclosporin A was used as a concomitant drug in 94.44 % of the patients. At two years of follow up, 66.7 % showed a response and the mortality rate was 11.1 %. Conclusion: The results of this case series substantiate the effectiveness of immunosuppressive therapy with a low-cost preparation of horse antithymocyte globulin (Thymogam) along with cyclosporin A in the management of aplastic anaemia patients not suitable for bone marrow transplantation.

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

A common method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate, and antithymocyte globulin (ATG). The use of posttransplant cyclophosphamide (PTCy) showed promise in a prospective trial for MMUD HCT. We compared 1-year graft-versus-host disease-free, relapse-free survival (GRFS) in 128 recipients of prophylaxis based on tacrolimus/methotrexate/ATG (ATG group, n = 46) vs PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, n = 82) after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥1 locus among HLA-A, HLA-B, HLA-C, and HLA-DRB1 were included. The 2 groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% vs 26%; P = .01) and >1 locus HLA-mismatched (30.5% vs 2.2%; P = .001) grafts. The 1-year GRFS was 16% (95% confidence interval (CI): 8%-31%) vs 54% (95% CI: 44%-66%; P < .001) in the ATG and PTCy groups, respectively. The multivariable adjusted hazard ratio for GRFS was 0.34 (95% CI: 0.21-0.55; P < .001) with the use of PTCy. The 1-year overall survival in the ATG group was 45% (95% CI: 32%-62%) vs 75% (95% CI: 66%-85%) in the PTCy group (P < .001). Relapse incidence was similar. One-year nonrelapse mortality was greater after ATG-based prophylaxis: 38% (95% CI: 23%-52%) vs 16% (95 CI: 9%-25%), P < .001. In summary, PTCy-based prophylaxis resulted in superior GRFS and overall survival in recipients of MMUD.

Key Clinical Message: This report describes a rare case of developing Guillain–Barre syndrome (GBS) following receiving rabbit antithymocyte globulin (ATG) after kidney transplantation to prevent acute allograft rejection in a 34‐year‐old man. The patient presented severe pain in the right temporomandibular joint, fever, chills, myalgia, polyarthralgia, and bone pain. Twelve hours later, he developed quadriplegia, paresthesia, and a limited range of active motions in all extremities. No antecedent viral or bacterial infection was identified. The EMG/NCV evaluation displayed acute inflammatory sensory‐motor polyneuropathy. After the administration of GBS treatment, the neurologic symptoms started to improve. Over a few days, the reflexes came back completely, and the patient was able to walk. To our knowledge, this is the second case report of ATG‐related GBS after kidney transplantation. [ABSTRACT FROM AUTHOR]

Key Clinical Message This report describes a rare case of developing Guillain–Barre syndrome (GBS) following receiving rabbit antithymocyte globulin (ATG) after kidney transplantation to prevent acute allograft rejection in a 34‐year‐old man. The patient presented severe pain in the right temporomandibular joint, fever, chills, myalgia, polyarthralgia, and bone pain. Twelve hours later, he developed quadriplegia, paresthesia, and a limited range of active motions in all extremities. No antecedent viral or bacterial infection was identified. The EMG/NCV evaluation displayed acute inflammatory sensory‐motor polyneuropathy. After the administration of GBS treatment, the neurologic symptoms started to improve. Over a few days, the reflexes came back completely, and the patient was able to walk. To our knowledge, this is the second case report of ATG‐related GBS after kidney transplantation.

Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [-0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (-0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.

Depletional induction using antithymocyte globulin (ATG) reduces rates of acute rejection in adult kidney transplant recipients, yet little is known about its effects in children. Using a longitudinal cohort of 103 patients in the Immune Development in Pediatric Transplant (IMPACT) study, we compared T cell phenotypes after ATG or non-ATG induction. We examined the effects of ATG on the early clinical outcomes of alloimmune events (development of de novo donor specific antibody and/or biopsy proven rejection) and infection events (viremia/viral infections). Long-term patient and graft outcomes were examined using the Scientific Registry of Transplant Recipients. After ATG induction, although absolute counts of CD4 and CD8 T cells were lower, patients had higher percentages of CD4 and CD8 memory T cells with a concomitant decrease in frequency of naïve T cells compared to non-ATG induction. In adjusted and unadjusted models, ATG induction was associated with increased early event-free survival, with no difference in long-term patient or allograft survival. Decreased CD4+ naïve and increased CD4+ effector memory T cell frequencies were associated with improved clinical outcomes. Though immunologic parameters are drastically altered with ATG induction, long-term clinical benefits remain unclear in pediatric patients.

BACKGROUND: Hepatitis C virus-positive (HCV+) kidney transplant (KT) recipients are at increased risks of rejection and graft failure. The optimal induction agent for this population remains controversial, particularly regarding concerns that antithymocyte globulin (ATG) might increase HCV-related complications. METHODS: Using Scientific Registry of Transplant Recipients and Medicare claims data, we studied 6780 HCV+ and 139 681 HCV- KT recipients in 1999-2016 who received ATG or interleukin-2 receptor antagonist (IL2RA) for induction. We first examined the association of recipient HCV status with receiving ATG (versus IL2RA) using multilevel logistic regression. Then, we studied the association of ATG (versus IL2RA) with KT outcomes (rejection, graft failure, and death) and hepatic complications (liver transplant registration and cirrhosis) among HCV+ recipients using logistic and Cox regression. RESULTS: HCV+ recipients were less likely to receive ATG than HCV- recipients (living donor, adjusted odds ratio [aOR] = 0.640.770.91; deceased donor, aOR = 0.710.810.92). In contrast, HCV+ recipients who received ATG were at lower risk of acute rejection compared to those who received IL2RA (1-y crude incidence = 11.6% versus 12.6%; aOR = 0.680.820.99). There was no significant difference in the risks of graft failure (adjusted hazard ratio [aHR] = 0.861.001.17), death (aHR = 0.850.951.07), liver transplant registration (aHR = 0.580.971.61), and cirrhosis (aHR = 0.730.921.16). CONCLUSIONS: Our findings suggest that ATG, as compared to IL2RA, may lower the risk of acute rejection without increasing hepatic complications in HCV+ KT recipients. Given the higher rates of acute rejection in this population, ATG appears to be safe and reasonable for HCV+ recipients.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

ObjectiveA pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration

Disseminated acanthamoebiasis is a rare, often fatal, infection most commonly affecting immunocompromised patients. We report a case involving sinuses, skin, and bone in a 60-year-old woman 5 months after heart transplantation. She improved with a combination of flucytosine, fluconazole, miltefosine, and decreased immunosuppression. To our knowledge, this is the first case of successfully treated disseminated acanthamoebiasis in a heart transplant recipient and only the second successful use of miltefosine for this infection among solid organ transplant recipients. Acanthamoeba infection should be considered in transplant recipients with evidence of skin, central nervous system, and sinus infections that are unresponsive to antibiotics. Miltefosine may represent an effective component of a multidrug therapeutic regimen for the treatment of this amoebic infection.

Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves β-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "super responders" (24-month C-peptide ≥ baseline), and "nonresponders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24 months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG+G-CSF demonstrated reduced CD4+ T cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ effector memory T cells (Tem), CD4+PD-1+ central memory T cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24 months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.

Background: Immunosuppressive therapy is the standard management of adults with aplastic anaemia. Antithymocyte globulin is used as first-line treatment of patients not eligible for bone marrow transplantation. This being a rare disease, available evidence in India is scarce. This study aimed to present experience in treating adult aplastic anaemia patients by immunosuppressive therapy using antithymocyte globulin-equine (Thymogam) in two tertiary care centres of northeast India., Methods: This case series was conducted at the Health city hospital, Guwahati, and Excel Care Hospital, Guwahati from 2018 to 2020. Eighteen adult aplastic anaemia patients who were treated by immunosuppressive therapy with antithymocyte globulin-equine (Thymogam) and followed up for two years were included. Treatment response and relapse are described., Results: All the 18 patients, (14 severe, four very severe) were uniformly treated with immunosuppressive therapy (Thymogam 40 mg/kg/d for four days with oral Cyclosporine from Day-1). Cyclosporin A was used as a concomitant drug in 94.44 % of the patients. At two years of follow up, 66.7 % showed a response and the mortality rate was 11.1 %., Conclusion: The results of this case series substantiate the effectiveness of immunosuppressive therapy with a low-cost preparation of horse antithymocyte globulin (Thymogam) along with cyclosporin A in the management of aplastic anaemia patients not suitable for bone marrow transplantation., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Aims/hypothesisType 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years.MethodsA multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses.ResultsFifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections.Conclusions/interpretationA brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study.Trial registrationClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.orgFundingNational Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).

Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

BackgroundAllogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.Methods and findingsThe study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.ConclusionsThe present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

Introduction: The rising prevalence of global end-stage renal disease (ESRD) is a significant health concern, especially among children. Although renal replacement therapy is available, children with ESRD are at an increased risk of mortality. Kidney transplantation is the preferred modality of treatment and surpasses renal replacement therapy in terms of survival. However, pediatric renal transplantation could prove difficult due to factors like smaller recipients and donor-recipient mismatches leading to higher complications., Materials and Methods: A retrospective single-group case series study was conducted on children with ESRD who were planned to undergo kidney transplantation from living donors between 2015 and 2021. The data was collected from two centers in the city of Sulaymaniyah., Results: The study comprised a predominantly male patient population, with a total of 39 individuals (n = 39) and 13 female patients. The donors were mostly males between 25-40 years old. The majority of participants were 15-18 years old. In majority of the patients Thymoglobulin was the immunosuppressive agent used in induction. The most common etiology for renal failure was reflux nephropathy and artery anastomosis was performed to the external iliac artery in the majority of patients. Only 9 patients had complications following the transplantation and 3 patients had an episode of acute rejection., Conclusions: Renal transplantation is the preferred treatment of renal failure in pediatric patients in the city of Sulaymaniyah. The most common etiology for pediatric renal failure was reflux nephropathy which was different from the findings of North American Pediatric Renal Trials and Collaborative Studies.

Rabbit anti-human T lymphocyte globulin (ATLG) and anti-thymocyte globulin (ATG) are commonly used for graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT). Yet, their efficacy and safety have seldom been compared in hematological malignancies with haploidentical HSCT. A retrospective analysis with 28 ATLG (total dosage, 20-30 mg/kg) and 18 ATG (total dosage, 8-10 mg/kg) patients were performed. The cumulative incidences of chronic GVHD and relapse were comparable between both groups. ATLG showed a trend towards a lower acute GVHD incidence (28.6% vs. 44.4%, P = 0.242) and 3-year non-relapse mortality (10.7% vs. 27.8%, P = 0.160), and had a significantly higher 3-year overall survival (OS, 64.3% vs. 33.3%, P = 0.033) and GVHD-free and relapse-free survival (GRFS, 32.1% vs. 11.1%, P = 0.045) compared with ATG. Multivariate Cox regression analysis demonstrated ATLG was independently associated with a favorable OS (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.16-0.86, P = 0.020) and GRFS (HR = 0.51, 95%CI: 0.26-1.00, P = 0.051). Furthermore, ATLG had a lower risk of fever (25.0% vs. 61.1%, P = 0.014) and hemorrhage cystitis (7.1% vs. 38.9%, P = 0.008) than ATG-T. In conclusion, ATLG confers more survival benefit and a better safety profile than ATG and can be used in hematological malignancies with haploidentical HSCT. Prospective designed trials with a larger sample size are warranted to confirm the results in the future., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background Aims: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT., Methods: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses., Results: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods., Conclusions: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method., Competing Interests: Declaration of competing interest KJC: research support: Novartis, Celgene, Cellectis, Atara Bio; consultant: Novartis, Atara Bio. SEP: support for the conduct of clinical trials: AlloVir, Jasper Therapeutics, Atara Biotherapeutics; consultation (last 24 months) CellEvolve, ADMA, Regeneron; intellectual property related to the use of third-party VSTs licensed to Atara Biotherapeutics with all rights assigned to Memorial Sloan Kettering Cancer Center. RJO: royalties following licensure of EBV-specific T-cell bank by Atara Biotherapeutics, research support and consultant fees from Atara Biotherapeutics. JJB: consulting Sobi, Bluebird Bio, Avrobio, BlueRock, SmartImmune, Sanofi, Omeros, Advanced Clinical (DMC Chair). All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The technique of αβ T cell depletion (αβTCD) is a well-established method of hematopoietic stem cell transplantation (HSCT) for children with acute leukemia owing to the low rates of graft-versus-host disease and nonrelapse mortality (NRM). The graft-versus-leukemia effect is generally ascribed to natural killer (NK) cells conserved within the graft. It is not known whether NK-related factors affect the outcome of αβTCD HSCT, however. The aim of this retrospective study was to explore the impact of NK alloreactivity (based on donor-recipient killer immunoglobulin-like receptor [KIR] mismatch), graft NK cell dose, and blood NK cell recovery on day +30 post-HSCT on the incidences of leukemia relapse and NRM. The pediatric acute leukemia cohort comprised 295 patients who underwent their first HSCT from a haploidentical donor in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (acute lymphoblastic leukemia [ALL]/acute myeloid leukemia [AML]), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less than versus greater than the median value), and blood NK cell recovery on day +30 post-HSCT (less than versus greater than the median value). We also investigated the influence of serotherapy (antithymocyte globulin [ATG] group) versus abatacept + tocilizumab combination [aba+toci] group) on relapse risk in the context of KIR mismatch. The risks of relapse and NRM were calculated by the cumulative risk method, and groups were compared using the Gray test. Multivariate analysis revealed no apparent impact of predicted NK alloreactivity or any other studied NK cell-related factors for the entire cohort. For patients with AML, a significantly higher relapse risk associated with high NK cell graft content on the background of no predicted KIR mismatch (P = .002) was shown. Multivariate analysis confirmed this finding (P = .018); on the other hand, for the KIR-mismatched patients, there was a trend toward a lower risk of relapse associated with high NK cell dose. The use of ATG was associated with a trend toward reduced relapse risk (P = .074) in the AML patients. There was no significant impact of NK-related factors in the ALL patients. Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in our cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as graft-versus-leukemia effectors., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

During hematopoietic stem cell transplantation (HSCT), ATG depletes T cells in-vivo to improve engraftment and prevent graft-versus-host disease (GVHD). Here, we compared the clinical efficacy of two different types of ATGs: thymoglobulin and anti-human T-lymphocyte immunoglobulin (Grafalon). A total of 469 patients who received haploidentical transplantation were enrolled in this retrospective study. We applied a propensity score (PS)-matched analysis and 209 patients were assigned to each group. Clinical outcomes were compared between two groups and primary outcome was overall survival (OS). There was no significant difference in OS between two groups. Within the first 180 days after HSCT, Grafalon was associated with lower incidences of Epstein-Barr virus (EBV) viremia (31.6 vs. 54.5%, P < 0.0001) and cytomegalovirus viremia (CMV) viremia (54.5 vs. 67.9%, P = 0.005) compared to thymoglobulin. Patients receiving Grafalon had a higher rate of moderate/severe chronic GVHD (26.3 vs. 18.2%, P = 0.046). However, the incidences of engraftment failure, grade II-IV acute GVHD, relapse, non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) did not differ greatly between groups. In the subgroup analysis, Grafalon improved the OS of lymphoid malignancies with young ages (< 40 years old) (HR, 0.55; P = 0.04) or with a high/very high disease risk index (HR, 0.36; P = 0.04). In the myeloid cohort, Grafalon reduced NRM in the patients who received non-female for male transplantation grafts (HR, 0.17; P = 0.02). Our results suggest the two types of ATG may differentially influence transplant outcomes and it may optimize ATG selection according to the condition of patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Antihuman thymocyte immunoglobulin, used as an induction agent in renal transplantation, is of two types - thymoglobulin and grafalon (formerly ATG-Fresenius). In this study, we compared outcomes with these two agents. Methods: This was a single-center retrospective study of patients transplanted from January 2017 to October 2019, who received either grafalon or thymoglobulin induction. Grafalon or thymoglobulin was given at 6 and 3 mg/kg, respectively, followed by standard triple immunosuppression of tacrolimus, MMF, and prednisolone. Results: Median follow up was 22 (3-36) months. Thymoglobulin was given to 255 patients, whereas 78 patients received grafalon. Baseline demographics were similar between the two groups although significantly more patients in the grafalon group received ABO incompatible transplant (15% vs. 4.3%; P = 0.002). Patient survival was similar between the two groups (99% in grafalon vs. 98.8% in thymoglobulin; P = 1.0). Death censored graft survival was also similar (99% in grafalon vs. 100% in thymoglobulin; P = 0.23). Biopsy proven acute rejection (BPAR) was significantly higher in the grafalon group (12.8% vs. 5.1%, P = 0.04). The significance persisted after multivariable regression analysis (P = 0.02). Other outcomes such as infection rate and estimated glomerular filtration rate on last follow up were comparable between the two groups. Conclusions: Grafalon (6 mg/kg dose) when used as an induction agent was associated with significantly higher rate of BPARs as compared to thymoglobulin (3 mg/kg dose) although with comparable short-term patient and death censored graft survival, graft function, and infection rates. [ABSTRACT FROM AUTHOR]

BackgroundPrevious efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and

Background/Aims Anti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy. Methods We retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome. Results Valacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis. Conclusions In conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR.

BackgroundType 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.MethodsFor this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.FindingsBetween Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.InterpretationOur findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.

Humoral immunity emerges as a risk factor for graft failure after visceral transplantation (VTx) and development of donor-specific anti-HLA antibodies (DSAs) has been linked with poor outcomes. In most cases, a simultaneous liver transplant can be safely performed in sensitized patients with DSA and appears protective against lymphocytotoxic antibodies. We investigated the incidence of acute (AR) and chronic rejection (CR) in 32 VTx without any B cell-depleting pre-treatment (6 isolated intestinal transplants (IT) and 26 liver-containing, multivisceral transplants (MVT) and assessed the presence of donor-specific antibodies (DSA) pre- and post-transplantation. Twenty-one patients (65 %) developed AR, 15 (57 %) of the MVT and 6 (100 %) of the IT (p = 0.05). CR occurred in 4 IT (60 %, p < 0.001). At one month, de novo DSA were present in 71 % of VTx (66 % MVT vs 100 % IT, p = 0.09). At the last available follow-up, 69 % of the MVT and 50 % of the IT patients were DSA-free. De novo DSA seemed more persistent (7/19, 37 %) than pre-Tx DSA (1/6, 17 %; p = n.s.), de novo DSA were more frequently specific for HLA class II than class I, 16/19 (84 %) vs. 7/19 (37 %; p = 0.003), and HLA-DQ was their most frequent target HLA. DQ mismatches appeared to be a risk factor for developing de novo DSA. In conclusion, liver-containing visceral allografts have superior short- and long-term outcomes compared with liver-free allografts. De novo DSA develop early and frequently after VTx performed without B cell-depleting induction therapy, but the exact role of DSA in the pathogenesis of rejection remains unclear., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Significance Statement: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist., Background: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization., Methods: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively., Results: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted., Conclusions: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity., Clinical Trial Registration Number: NCT04294459 ., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Introduction: The process of immunization following vaccination in humans bears similarities to that of immunization with allografts. Whereas vaccination aims to elicit a rapid response, in the transplant recipient, immunosuppressants slow the immunization to alloantigens. The induction of CD4+CXCR5+ T follicular helper (Tfh) cells has been shown to correlate with the success of vaccine immunization., Method: We studied a cohort of 65 transplant recipients who underwent histological evaluation concurrent with PBMC isolation and follow-up sampling to investigate the phenotypic profiles in the blood and allotissue and analyze their association with clinical events., Results: The proportion of circulating Tfh cells was heterogeneous over time. Patients in whom this compartment increased had lower CCR7-PD1+CD4+CXCR5+ T cells during follow-up. These patients exhibited more alloreactive CD4+ T cells using HLA-DR-specific tetramers and a greater proportion of detectable circulating plasmablasts than the controls. Examination of baseline biopsies revealed that expansion of the circulating Tfh compartment did not follow prior intragraft leukocyte infiltration. However, multicolor immunofluorescence microscopy of the grafts showed a greater proportion of CXCR5+ T cells than in the controls. CD4+CXCR5+ cells were predominantly PD1+ and were in close contact with B cells in situ. Despite clinical stability at baseline, circulating Tfh expansion was associated with a higher risk of a composite of anti-HLA donor-specific antibodies, rejection, lower graft function, or graft loss., Conclusion: In otherwise stable patients post-transplant, circulating Tfh expansion can identify ongoing alloreactivity, detectable before allograft injury. Tfh expansion is relevant clinically because it predicts poor graft prognosis. These findings have implications for immune surveillance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Désy, Béland, Thivierge, Marcoux, Desgagnés, Bouchard-Boivin, Gama, Riopel, Latulippe and De Serres.)

Background: The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring., Methods: This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed., Results: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II., Conclusion: Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients., (© 2023 Wiley Periodicals LLC.)

Abstract: B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

High titer of donor-specific antibodies (DSAs) increases the risk of graft rejection after mismatched related hematopoietic cell transplantation (HCT). There are no data regarding the incidence of anti-HLA recipient-specific antibodies (RSAs) and their role after transplantation. Here we aimed to identify the incidence of RSAs in a mismatched related hematopoietic cell donor population and their possible impact on immune-mediated complications, such as acute graft-versus-host disease (aGVHD), and complications resulting from endothelial injury, such as transplantation-associated thrombotic microangiopathy (TA-TMA) and veno-occlusive disease (VOD). We prospectively analyzed the incidence of anti-HLA antibodies in 28 mismatched related pairs of recipients and their donors who underwent HCT at our center between 2020 and 2022. In positive samples screened for anti-HLA class I and/or II antibodies, the specificity of the HLA antibodies was analyzed. All recipients had a hematologic malignancy and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were tested for TA-TMA and aGVHD development during routine post-transplantation visits up to 100 days post-transplantation. We used modified Jodele criteria for TA-TMA diagnosis, and based aGVHD grading on the MAGIC criteria. VOD was assessed using the European Society for Blood and Marrow Transplantation. Anti-HLA antibodies were detected in 12 donors (43%) and in 9 recipients (32%). There were no significant differences between donors and recipients according to age (median, 42 years [range, 17 to 69 years] versus 39 years [range, 8 to 68 years]), sex, or pregnancy history. No transfusion history was noted in the donor group (P < .05). RSA antibodies were present more often than DSAs and were detected in 9 out of 12 (75%) anti-HLA-positive donors and in only 2 out of 9 (22%) recipients, respectively (P < .05). During the follow-up, 11 patients (39%) developed aGVHD, including grade I-II in 9 (32%) and grade III-IV in 2 (7%). Twelve patients (43%) met the criteria for TA-TMA, and only 1 patient (3.5%) was diagnosed with VOD by day 100 post-HCT. RSAs were detected significantly more often in the TA-TMA group; among 12 patients diagnosed with TA-TMA, 7 (58%) had RSAs (P < .05). We did not find a correlation between RSAs and aGVHD. The patient with VOD did not have an RSA-positive donor. There was no difference in membrane attack complex (MAC) concentration in the RSA-positive group on day 30 and day 60 post-HCT; however, there was a trend toward higher MAC concentration in the RSA-positive group on day 100 (median, 912 ng/mL [range, 788 to 1120 ng/mL] versus 616 ng/mL [range, 352 to 1244 ng/mL]; P = .055). Patients with RSA suffered more often from platelet and red blood cell decreases or transfusion refractoriness, and increased lactate dehydrogenase activity was observed in all RSA-positive cases. The donor immune status and the presence of RSA may be associated with higher rates of TA-TMA in mismatched HCT recipients. Antibody-mediated complement activation might be an additional factor influencing TA-TMA occurrence., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation., Methods: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established., Results: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P  = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P  = 0.039) were observed in the study cohort., Conclusions: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients. Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation. Thymoglobulin induction led to an immediate and significant decrease of all T cells and NK cells, but not B cells or monocytes. CD8(+) T cells recovered to near pretransplant level by 4 weeks post-transplant. CD4(+) T cells remained at less than 30% of pretransplant level for the entire study period of 78 weeks. Both CD4(+) and CD8(+) T cells showed reduced cytokine production after recovery. Deletion of CD4(+) FOXP3(+) HELIOS(+) regulatory T cells (Tregs) was less profound than that of CD4(+) FOXP3(-) cells, thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin-treated patients. In contrast, the percentages of Tregs and their expression of FOXP3 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56% of the pretransplant level. Thus, thymoglobulin-induced deletion of T cells led to significant and long-lasting alterations of the T-cell compartment characterized by a preservation of Tregs and long-lasting reduction in CD4(+) , and potentially pathogenic, T cells.

Background: The expression of major histocompatibility complex class II ( MhcII ) molecules on B cells is required for the development of germinal centers (GCs) in lymphoid follicles; the primary sites for the generation of T-cell-dependent (TD) antibody responses. Peyer's patches (PPs) are secondary lymphoid tissues (SLOs) in the small intestine (SI) that give rise to high-affinity, TD antibodies (mainly immunoglobulin A (IgA)) generated against the microbiota. While several studies have demonstrated that MhcII antigen presentation by other immune cells coordinate TD IgA responses and regulate microbiota composition, whether or not B-cell-specific MhcII influences gut microbial ecology is unknown., Methods: Here, we developed a novel Rag1 -/- adoptive co-transfer model to answer this question. In this model, Rag1 -/- mice were reconstituted with naïve CD4 + T cells and either MhcII -sufficient or MhcII -deficient naïve B cells. Subsequent to this, resulting shifts in microbiota composition was characterized via 16S rRNA gene sequencing of SI-resident and fecal bacterial communities., Results: Results from our experiments indicate that SLO development and reconstitution of an anti-commensal TD IgA response can be induced in Rag1 -/- mice receiving T cells and MhcII -sufficient B cells, but not in mice receiving T cells and MhcII -deficient B cells. Results from our 16S experiments confirmed that adaptive immunity is a relevant host factor shaping microbial ecology in the gut, and that its impact was most pronounced on SI-resident bacterial communities., Conclusion: Our data also clearly establishes that MhcII -mediated cognate interactions between B cells and T cells regulates this effect by maintaining species richness in the gut, which is a phenotype commonly associated with good health. Finally, contrary to expectations, our experimental results indicate that IgA was not responsible for driving any of the effects on the microbiota ascribed to the loss of B cell-specific MhcII . Collectively, results from our experiments support that MhcII -mediated antigen presentation by B cells regulates microbiota composition and promotes species richness through an IgA-independent mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Roland, Peacock, Hall, Mohammed, Ball, Jolly, Alexeev, Dopkins, Nagarkatti, Nagarkatti and Kubinak.)

Chimeric antigen receptor T-cell therapy and bispecific T-cell recruiting antibodies have transformed the treatment landscape for relapsed/refractory multiple myeloma, with B-cell maturation antigen being the most common target and other targets in clinical development. However, these therapies are associated with unique and severe toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity, cytopenias, and infection. In addition, immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS), which exhibits overlap between CRS and HLH, can be challenging to diagnose and treat. In this review, we provide an overview of toxicities associated with novel immunotherapies for treatment of multiple myeloma and describe management recommendations. The pathophysiology and risk factors behind these toxicities are not yet comprehensively understood. Based on consensus recommendations, treatment for CRS consists of tocilizumab and steroids, while treatment for ICANS includes steroids and anakinra in severe cases. Management of cytopenias and infection is similar to post-hematopoietic cell transplantation principles with antimicrobial prophylaxis, growth factor support, immunoglobulin replacement, and vaccinations. In contrast, effective treatments for delayed neurotoxicity and IEC-HS are lacking, although steroids and anakinra are commonly used. Management of all these toxicities should include a broad differential and multidisciplinary collaboration with infectious diseases, neurology, and/or critical care providers., (Copyright © 2023 by The American Society of Hematology.)

The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction., Competing Interests: Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which seriously affects the prognosis of patients. At present, a new regimen of post-transplantation cyclophosphamide (PTCy) combined with antithymocyte globulin (ATG) has been used to prevent GVHD, indicating that PTCy combined with ATG may have a good effect on the prevention of GVHD in different types of transplantation. However, the mechanism of this regimen, its effect on immune reconstitution and viral reactivation still needs to be further studied. Therefore, this article briefly reviews the research progress of PTCy combined with ATG in preventing GVHD after HSCT.

The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Purpose: There are no clear guidelines on how to handle immunosuppression in lung transplant recipients (LTRs) infected by SARS-CoV-2. Antimetabolite reduction with corticosteroid escalation is the most frequent strategy. The aim of this study was to determine the effect of this therapeutic approach on the incidence of de novo donor specific-antibodies (dnDSA)., Methods: We retrospectively analysed a cohort of 27 LTRs diagnosed with SARS-CoV-2 infection between September 2020 and April 2021 with available anti-HLA antibodies screening before and after infection. Managed as per the centre's SARS-CoV-2 protocol, the treatment modalities included specific virostatic treatment, convalescent plasma administration, reduction or discontinuation of mycophenolate and transient corticosteroid escalation initiated in the second week post-infection., Results: All 27 patients received virostatics: 15 (55.6%) remdesivir and 12 (44.4%) favipiravir. In addition, 18 patients (66.7%) underwent convalescent plasma therapy. Of the 27 patients, 25 (92.6%) received mycophenolate as a part of their maintenance immunosuppressive regimen, which was temporarily reduced in 10 (37%) and discontinued in 15 LTRs (55.6%), the median resumption times for mycophenolate daily doses of at least 1000 mg being 13 days (IQR 11.0-63.5) and 59 days (IQR 26.0-130.0), respectively. Corticosteroids were escalated in 25 patients (92.6%), of whom 9 (33.3%) received IV methylprednisolone (median 80 mg/day; IQR 80-187.5) and 16 (59.3%) had oral prednisone adjusted (median 20 mg/day; IQR 16.3-38.8). The median time to revert to the corticosteroid dosage of ≤20 mg/day was 42 days (IQR 36.0-87.0). Notably, no dnDSA were detected in any LTR between 1 and 9 months from the onset of the SARS-CoV-2 infection., Conclusion: Our findings suggest that antimetabolite cessation with a transient corticosteroid escalation is a safe therapeutic strategy regarding anti-HLA dynamics in SARS-CoV-2 infected LTRs., Competing Interests: Declaration of Competing Interest None of the authors of this manuscript have any conflicts of interest to disclose in relation to this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical haematopoietic stem cell transplantation (Haplo-HSCT). Double filtration plasmapheresis (DFPP) avoids the unnecessary loss of plasma proteins and increases the efficiency of purification. To investigate the effectiveness of the desensitization protocol including DFPP and rituximab, we conducted a nested case-control study. Thirty-three patients who had positive DSA were desensitized by the protocol and 99 patients with negative DSA were randomly matched as control. The median DSA mean fluorescence intensity values before and after DFPP treatment were 7505.88 ± 4424.38 versus 2013.29 ± 4067.22 (p < 0.001). All patients in DSA group achieved haematopoietic reconstitution and the median neutrophils and platelets engraftment times were 13 (10-21) and 13 (10-29) days respectively. Although the cumulative incidence of II-IV aGVHD (41.4% vs. 28.1%) and 3-year moderate to severe cGVHD (16.8% vs. 7.2%) were higher in DSA cohort than in the control, no statistical significance was observed. The 3-year non-relapse mortality and the overall survival were 6.39% and 72.0%, respectively, in the DSA cohort, which were comparable to the negative control. In conclusion, DFPP and rituximab could be effectively used for desensitization and overcome the negative effects of DSA in Haplo-HSCT., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis., Methods: In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87)., Results: Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1)., Conclusions: Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications., Competing Interests: Conflict of interest . E. H. serves on the advisory board for and reports consulting fees from Maat Pharma and Pharmabiom. He also reports payment for educational flyers from Novartis and participation on a Data and Safety Monitoring Board (DSMB) for Medac. D. Wolff declares honoraria from Novartis, Gilead, Takeda, Incyte, Sanofi, and Mallinckrodt and grants or contracts from Novartis; consulting fees from Sanofi and Incyte; support for attending meetings and/or travel from Takeda; participation on a DSMB or advisory board from Behring and Novartis. W. H. declares honoraria from Amgen, Novartis, Janssen Oncology, and Gilead. B. S. reports a role as Chair, German Society of Infectious Diseases (unpaid). D. Weber reports the following grants or contracts unrelated to this work: Deutsche Forschungsgemeinschaft (DFG [German Research Foundation]; project ID 324392634; TRR 221. H. P. reports consulting fees and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Abbvie, Bristol-Myers Squibb, Novartis, Servier, Pfizer, Astellas, and Gilead/Kite; support for attending meetings and/or travel from Abbvie, BMS, Novartis, Servier, Pfizer, Astellas, Amgen, and Jazz; participation on a DSMB or advisory board from Pfizer and Abbvie. M. W. reports grants or contracts unrelated to this work from the German Ministry of Education and Research (13GW0558D). M. E. reports a role as a Directory Board Member from Leibniz Institute for Immunotherapy. None of these declarations are related to the presented work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG-targeted dosing strategy in adult unmanipulated haplo-PBSCT. ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on -3 days and -2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo-PBSCT patients were enrolled and 63 of them were evaluable with a median follow-up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1-year disease-free survival was 82.5%, overall survival was 92.1%, and CD4+ T-cell reconstruction on +100 days was 76.8%. The most common severe regimen-associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo-PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p < .001; EBV reactivation: 76.0%, p = .024; CD4 + T-cell reconstruction: 54.1%, p = .040). In conclusion, ATG-targeted dosing strategy reduced CMV/EBV reactivation and improved survival without increasing GVHD after haplo-PBSCT. These advantages may be associated with accelerated immune reconstitution., (© 2023 Wiley Periodicals LLC.)

Introduction: Post-transplant diabetes mellitus (PTDM) is a common complication among cardiac transplant recipients, causing diabetes-related complications and death. While certain maintenance immunosuppressive drugs increase PTDM risk, it is unclear whether induction immunosuppression can do the same. Therefore, we evaluated whether induction immunosuppression with IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, or Alemtuzumab given in the peri-transplant period is associated with PTDM., Methods: We used the Scientific Registry of Transplant Recipients database to conduct a cohort study of US adults who received cardiac transplants between January 2008-December 2018. We excluded patients with prior or multiple organ transplants and those with a history of diabetes, resulting in 17,142 recipients. We created propensity-matched cohorts (n=7,412) using predictors of induction immunosuppression and examined the association between post-transplant diabetes and induction immunosuppression by estimating hazard ratios using Cox proportional-hazards models., Results: In the propensity-matched cohort, the average age was 52.5 (SD=13.2) years, 28.7% were female and 3,706 received induction immunosuppression. There were 867 incident cases of PTDM during 26,710 person-years of follow-up (32.5 cases/1,000 person-years). There was no association between induction immunosuppression and post-transplant diabetes (Hazard Ratio= 1.04, 95% confidence interval 0.91 - 1.19). Similarly, no associations were observed for each class of induction immunosuppression agents and post-transplant diabetes., Conclusion: The use of contemporary induction immunosuppression in cardiac transplant patients was not associated with post-transplant diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gupta, Mostofsky, Motiwala, Hage and Mittleman.)

This is an observational multicentric cross-sectional study aiming at assessing the association between ABO blood groups and SARS-CoV-2 seroprevalence among the blood donors in Puglia region. Data on ABO and Rh blood groups and demographic characteristics were obtained from Blood Bank Information System. All donors were screened for SARS-CoV-2 IgG antibodies. Comparison of seroprevalence among blood groups and the association between the recorded variables and seroprevalence were evaluated. A total of 35,709 donors from 22 centers were included, with a seroprevalence of 6.8%. The distribution of ABO phenotypes was blood type O (46.8%), A (34.0%), B (14.7%), and AB (4.5%). Among the 2416 donors reactive for SARS-CoV-2 IgG, the prevalent phenotype was blood type O (43.1%), followed by A (37.7%), B (14.2%), and AB (5%). The seroprevalence of phenotype A and AB was 7.5%, followed by B (6.5%) and O (6.2%). According to the adjusted analysis, there was an increase in seroprevalence in groups A and AB, compared to group O, and an increase in males compared to females. A possible effect modification was observed after stratifying for sex (p = 0.0515). A significantly lower prevalence of blood type O was found compared to A and AB, whereas no association was observed between Rh factor and seroprevalence. We hypothesized that the A antigen present in blood type A and AB can play a role in the binding of SARS-CoV-2 to ACE2 receptors, resulting in an increased risk of infection. Furthermore, natural anti-A/anti-B antibodies produced in group O could block viral adhesion to cells and explain a lower risk of infection., (© 2023. The Author(s).)

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CsA) is the first-line therapy for acquired aplastic anemia (AA) in those not suitable for bone marrow transplant. Horse ATG (hATG) is preferred for this purpose, but its use is often impeded by shortages and costs. Being a rare disease, there is limited data on this therapy. This study aimed to evaluate this therapy in a large cohort of AA patients from western India. We retrospectively analyzed AA patients who received an indigenous preparation of hATG along with CsA as first-line treatment, between 2012 and 2015, at our center and evaluated the response, survival, and occurrence of adverse events. The response was further assessed separately for adults and children. During the period, 91 AA patients (4 non-severe, 57 severe and 30 very severe) were treated with IST. At 2 years, 23.5% adults and 39.1% children showed complete response and an overall of 68.1% cases became transfusion independent. More than half of the patients developed febrile neutropenia while roughly one sixth of the patients developed gum hypertrophy and/or hypertension. Two patients had clonal evolution. Mortality rate was calculated to be 31%; most common causes of death were infection and intracranial hemorrhage. The results of the study substantiate the effectiveness of IST in AA, using an inexpensive indigenous preparation of hATG along with CsA. [ABSTRACT FROM AUTHOR]