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Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH2-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH2-terminally truncated proteoforms CXCL8(6–77), CXCL8(8–77) and CXCL8(9–77), but also the partially inactivated CXCL8(10–77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9–77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs. [ABSTRACT FROM AUTHOR]

Alloimmunization remains a major obstacle to successful kidney transplantation, mainly due to the formation of anti-HLA antibodies. In recent years, non-HLA antibodies have emerged as additional immunologic factors that can potentially contribute to graft rejection. The aim of this study was to investigate the prevalence and specificity of both anti-HLA and non-HLA antibodies in patients with end-stage renal disease on a waiting list for kidney transplantation. Serum samples from 74 patients were analyzed using complement-dependent cytotoxicity and solid-phase assays. IgG anti-HLA antibodies were identified in 43.2% of participants, while IgG non-HLA antibodies were detected in 91.9%. The most frequent non-HLA antibodies included anti-ENO1 (28.4%), anti-FIBR1 (23.0%) and anti-PRKCZ (23.0%). A significant difference was found between the number of distinct IgG anti-HLA and IgG non-HLA antibody specificities. However, no significant correlation was found between the number of IgG non-HLA antibody specificities and previous alloimmunization events or dialysis treatments. These results suggest that non-HLA antibodies, although often overlooked, can sometimes play a critical role in transplant outcomes. Routine testing for non-HLA antibodies, in addition to mandatory anti-HLA antibody screening and identification, could improve immunologic risk assessment in transplant patients and post-transplant care. [ABSTRACT FROM AUTHOR]

The activation of naive T cells by mature dendritic cells (DCs) presenting allograft antigens marks a pivotal stage in triggering transplant rejection. A critical intervention in this process involves the administration of rapamycin, which disrupts the mTOR signaling pathway, thereby impeding DC maturation. Nevertheless, systemic administration of rapamycin faces challenges due to its limited bioavailability, non‐specific targeting, and notable side effects. To address these limitations, LNP@rapa (liposome‐encapsulated rapamycin) is developed, administered via subcutaneous injection. This formulation selectively targets lymph nodes, inhibiting DC maturation within these nodes and mitigating transplant rejection. This study validates the in vivo efficacy of LNP@rapa, demonstrating its ability to hinder DC maturation, reduce inflammatory cytokine secretion, and significantly prolong graft survival in two distinct mouse transplantation models. This study introduces an innovative strategy targeting lymph nodes to impede DC maturation, offering a promising approach to address transplant rejection. [ABSTRACT FROM AUTHOR]

The editorial in Frontiers in Immunology discusses the emerging field of immune metabolism in auto- and allo-immunity. The editorial highlights the critical link between metabolic pathways and immune responses, focusing on research articles related to autoimmune diseases like Systemic Lupus Erythematosus and Type 1 Diabetes Mellitus, as well as transplant immunology. The articles explore how metabolic changes in immune cells impact disease pathogenesis and potential therapeutic strategies. Additionally, the editorial discusses the role of proline metabolism in asthma and the potential of immune cell metabolism in transplant tolerance. [Extracted from the article]

Background: The renin-angiotensin-aldosterone system (RAAS) is responsible for a multitude of physiological functions, including immunological effects such as promotion of TGF-β and upregulation of IL-6 and IL-8 which are also implicated in the development of chronic lung allograft dysfunction (CLAD). Blockade of the RAAS pathway in pre-clinical models has demonstrated a decrease in these cytokines and pulmonary neutrophil recruitment. Objective: This study sought to evaluate whether use of RAAS inhibitor (RAASi) in lung transplant recipients impacted CLAD-free survival. Methods: In this retrospective, single-center study, 35 lung transplant recipients who received a RAASi post-transplant were compared to 70 lung transplant recipients not exposed to a RAASi and were followed for up to 5 years post-transplant. Results: The incidence of CLAD did not differ based on RAASi treatment (34.3% in RAASi vs 38.6%, P -value.668). This was confirmed with a multivariable Cox proportional hazards model with RAASi initiation as a time-varying covariate (RAASi hazard ratio of 1.01, P -value.986). Incidence of hyperkalemia and acute kidney injury were low in the RAASi group. Conclusions: This study demonstrated no association between post-transplant RAASi use and decreased risk of CLAD development. RAASi were also well tolerated in this patient population. [ABSTRACT FROM AUTHOR]

Relevance. Some achievements related to liver transplantation in the field of infectious complications, rejection treatment and surgical tactics have also contributed to improving patient survival. Nevertheless, it is true that the huge progress made in the field of transplantation is mainly due to the emergence of safe and effective immunosuppressive drugs. But complications from immunosuppressive drugs are still a significant problem and the ability to give up immunosuppressants altogether or significantly reduce the dose will help solve it. Aim: to present a review of the literature and to analyze the main aspects of immunotolerance in immunosuppressive therapy after liver transplantation. Materials and methods: Foreign and Russian literature on the topic of immunotolerance and immunosuppressive therapy was used. The search for literary data was carried out in international databases (PubMed/MedLine, ResearchGate), as well as in the scientific electronic library of Russia (eLIBRARY.RU ) for the period 2019– 2024. Conclusion. Undoubtedly, the rejection of immunosuppressive therapy is a brilliant prospect for recipients not only of the liver, but also of other donor organs, therefore, with the future development of interdisciplinary and multifactorial research, the use of various new experimental methods may provide more opportunities and theoretical guidance to find a way to achieve tolerance in liver transplantation.

Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and gd T cells, whereas TNFa signaling via NFkB was particularly active in regulatory T cells, gd T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation. [ABSTRACT FROM AUTHOR]

Introduction: Cytomegalovirus (CMV) infection is mainly associated with acute or chronic graft rejection in various solid organs. This study was conducted with the aim of evaluating the plasma viral load of CMV infection in postheart transplant patients and its correlation with the grading of cellular graft rejection in endomyocardial biopsies. Materials and Methods: In a cross-sectional study, 90 samples from 65 asymptomatic heart transplant recipients scheduled for routine endomyocardial biopsy were obtained. All the recipients had a history of positive serology for CMV infection before transplantation. Evaluation of their DNA was tracked using the polymerase chain reaction technique and the use of specific virus DNA primers, and based on this, the peak virus load (the number of virus copies per milliliter) was determined. A peak viral load >10,000 copies/mL was considered positive. Graft rejection grading was determined based on the ISHLT grading system. Results: The mean (standard deviation) age of the patients (37 men) was 67 (37.3) years. The graft rejection grading was as follows: 22.2% grade 0, 38.9% Quilty effect (QE), 35.6% grade 1, and 3.3% grade 2. The mean plasma viral load level of CMV infection was 2197.4 (1256.2) μg/μL, 1970.4 (1150.3) μg/μL, and 4567.2 (1669.1) μg/μL in grades 0, QE, and 1 and/or 2, respectively (P < 0.001). The virus load was significantly higher in those with higher grades of cellular rejection. Conclusion: The relationship between the plasma level of CMV viral load and the grading of cellular graft rejection in heart transplant patients could emphasize the role of CMV virus in the pathophysiology of graft rejection. A closer surveillance for CMV infection using the viral load is also recommended in particular in those who have higher grades of graft rejection.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection. [ABSTRACT FROM AUTHOR]

Background and Objectives: Endobiogeny is a global systems approach to human biology based on the concept that the endocrine system manages the metabolism. Biology of function (BoF) indices are diagnostic tools in endobiogenic medicine that reflect the action of the endocrine system on the cells and the metabolic activity of an organism. Kidney transplant recipients are a very specific patient population due to their constant use of immunosuppressive agents such as steroids and anamnesis of chronic kidney disease. The aim of this study was to assess the tendencies of endobiogenic BoF indices in a kidney transplant recipient population and to determine the relationship between BoF index values and histology-proven kidney transplant rejection. Materials and Methods: A total of 117 kidney transplant recipients undergoing surveillance or indication allograft biopsy were included in this study. Endobiogenic BoF indices were calculated from complete blood count tests taken before the kidney biopsy. Histology samples were evaluated by an experienced pathologist according to the Banff classification system. Clinical and follow-up data were collected from an electronic patient medical record system. Results: Overall, <35% of the patients had BoF index values assumed to be normal, according to the general population data. Additionally, >50% of the patients had lower-than-normal adaptation, leucocyte mobilization, genital, and adjusted genital ratio indices, while the Cata-Ana, genito-thyroid ratio, adrenal gland, and cortisol indices were increased in >50% of the transplant recipients. The adaptation index was significantly higher in patients with biopsy-proven transplant rejection and demonstrated an AUC value of 0.649 (95%CI 0.540–0.759) for discriminating rejectors from patients without transplant rejection. Conclusions: Most of the kidney transplant recipients had abnormal BoF index values, reflecting increased corticotropic effects on their cells. The adaptation index distinguished patients with biopsy-proven transplant rejection from those without it. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Non‐lupus full house nephropathy is a rare entity that is still poorly understood. It can complicate post‐transplant kidneys and result in a de novo process. Treatment is difficult but can be possibly achieved with optimization of immune suppression. Non‐lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, and C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognized but further studies are still needed to evaluate the incidence, etiologies, and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; it can cause AKI, CKD, or glomerular inflammations through an immune complex or autoimmune‐mediated damage. [ABSTRACT FROM AUTHOR]

Hepatitis C virus positive (HCV+) organ donors offer a viable strategy for expansion of the heart donor pool without an increased risk of recipient mortality. Cardiac magnetic resonance imaging (CMR) is an effective tool for graft surveillance in heart transplant (HT) recipients. However, there are no data comparing CMR findings in HT recipients based on donor HCV status. The aim of this propensity score matched case-control study was to evaluate baseline CMR characteristics of HCV+ HT recipients and HCV- HT recipients, as well as compare cardiac allograft structure, function, performance, and tissue characterization between groups. CMR normative values did not differ between groups in matched analysis. There were no significant differences in CMR-derived biventricular function, strain, late gadolinium enhancement, or myocardial tissue characteristics by parametric mapping. This study suggests CMR can be a valuable tool for surveillance in HCV+ HT patients, and abnormalities on imaging should not be attributed to HCV infection.

Background Pathologic diagnosis of antibody-mediated rejection (ABMR) in ABO-incompatible (ABOi) transplantation patients is often challenging because patients without ABMR are frequently immunopositive for C4d. The aim of this study was to determine whether C4d positivity with microvascular inflammation (MVI), in the absence of any detectable donor-specific antibodies (DSAs) in ABOi patients, could be considered as ABMR. Methods A retrospective study of 214 for-cause biopsies from 126 ABOi kidney transplantation patients was performed. Patients with MVI score of ≥2 and glomerulitis score of ≥1 (n = 62) were divided into three groups: the absolute ABMR group (DSA-positive, C4d-positive or C4d-negative; n = 36), the C4d-positive group (DSA-negative, C4d-positive; n = 22), and the C4d-negative group (DSA-negative, C4d-negative; n = 4). The Banff scores, estimated glomerular filtration rates (eGFRs), and graft failure rates were compared among groups. Results C4d-positive biopsies showed higher glomerulitis, peritubular capillaritis, and MVI scores compared with C4d-negative specimens. The C4d-positive group did not show significant differences in eGFRs and graft survival compared with the absolute ABMR group. Conclusion The results indicate that C4d positivity, MVI score of ≥2, and glomerulitis score of ≥1 in ABOi allograft biopsies may be categorized and treated as ABMR cases.

The microbial communities that inhabit our bodies have been increasingly linked to host physiology and pathophysiology. This microbiome, through its role in colonization resistance, influences the risk of infections after transplantation, including those caused by multidrug-resistant organisms. In addition, through both direct interactions with the host immune system and via the production of metabolites that impact local and systemic immunity, the microbiome plays an important role in the establishment of immune tolerance after transplantation, and conversely, in the development of graft-versus-host disease and graft rejection. This review offers a comprehensive overview of the evidence for the role of the microbiome in hematopoietic cell and solid organ transplant complications, drivers of microbiome shift during transplantation, and the potential of microbiome-based therapies to improve pediatric transplantation outcomes. [ABSTRACT FROM AUTHOR]

The development of autoimmune diseases and the rejection of transplanted organs are primarily caused by an exaggerated immune response to autoantigens or graft antigens. Achieving immune tolerance is crucial for the effective treatment of these conditions. However, traditional therapies often have limited therapeutic efficacy and can result in systemic toxic effects. The emergence of nanomedicine offers a promising avenue for addressing immune-related diseases. Among the various nanoparticle formulations, cationic nanoparticles have demonstrated significant potential in inducing immune tolerance. In this review, we provide an overview of the underlying mechanism of autoimmune disease and organ transplantation rejection. We then highlight the recent advancements and advantages of utilizing cationic nanoparticles for inducing immune tolerance in the treatment of autoimmune diseases and the prevention of transplant rejection. [Display omitted] • Important role of immunomodulation in autoimmune diseases and organ transplantation. • The great promises of cationic nanoparticles in inducing immune tolerance for related diseases therapy. • Illustration the design and optimization of cationic nanoparticles. • Advantages of cationic nanoparticles in modulating immune cell functions. [ABSTRACT FROM AUTHOR]

Key Clinical Message Non‐lupus full house nephropathy is a rare entity that is still poorly understood. It can complicate post‐transplant kidneys and result in a de novo process. Treatment is difficult but can be possibly achieved with optimization of immune suppression. Abstract Non‐lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, and C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognized but further studies are still needed to evaluate the incidence, etiologies, and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; it can cause AKI, CKD, or glomerular inflammations through an immune complex or autoimmune‐mediated damage.

ABSTRACTPrevious studies have shown that the gut microbiota and its metabolites are associated with the success of organ transplantation. However, the specific changes in the gut microbiota of lung transplant patients remain unclear. Hence, this study aimed to elucidate the interplay between the gut microbiota, metabolome, and lung transplantation outcomes. Using 16S metagenomics sequencing and untargeted metabolic profiling, we conducted a comprehensive analysis of gut microbial and metabolic alterations in lung transplant recipients relative to non-transplant group. Our findings revealed the predominance of Enterococcus and Streptococcus genera within the lung transplant cohort, accompanied by the significant reduction in Bacteroides, Epulopiscium, Faecalibacterium, and Prevotella abundance. In addition, a significant reduction in ATRA (all-trans retinoic acid) levels and suppression of IgA production were observed in lung transplant recipients, which were found to be closely associated with the Enterococcus genus. It was speculated that the association might have implications for the prognosis of lung transplant patients. Notably, the differences in gut microbial composition and metabolomic profiles between successful transplant recipients and those experiencing chronic rejection were not statistically significant. These novel insights shed light on the putative implications of the gut microbiota and metabolome in shaping lung transplantation outcomes, and provide a foundation for future investigations and targeted therapeutic interventions.IMPORTANCEThis study has profound implications for lung transplantation as it uncovers the important role of gut microbiota and metabolome in shaping transplantation outcomes. The identification of dominant bacterial genera, such as Enterococcus and Streptococcus, within the lung transplant cohort, along with the significant decrease in Bacteroides, Epulopiscium, Faecalibacterium, and Prevotella abundance, reveals potential microbial imbalances associated with lung transplantation. In addition, a significant reduction in ATRA (all-trans retinoic acid) levels and suppression of IgA production were observed in lung transplant recipients, which were found to be closely associated with the Enterococcus genus. It was speculated that the association might have implications for the prognosis of lung transplant patients. These findings hold immense clinical significance as they lay the groundwork for future research and targeted therapeutic interventions. Understanding the impact of the gut microbiota and metabolome on lung transplantation outcomes offers promising avenues for improving transplantation patient prognosis.

Introduction: Visual assessment of endomyocardial biopsy (EMB) specimens may result in errors due to the human factor and inability to obtain quantitative data on the intensity of immunohistochemical (IHC) reactions and severity of pathological changes in the heart transplant. Detailed digital characterization of EMB specimens based on automated or semi-automated computer-assisted morphometry improves the diagnostic accuracy of EMB. Objective: To develop a method of and algorithms for digital computer-assisted analysis of EMB specimens to quantify pathomorphological and immunophenotypic changes in the myocardium of patients with various types and grades of heart transplant rejection. Materials and methods: We studied 257 EMB specimens from 56 heart transplant recipients at Scientific Research Institute – Ochapovsky Regional Clinical Hospital No. 1 (Krasnodar, Russian Federation). Sections were stained with hematoxylin and eosin. We used the streptavidin-biotin method to determine the CD68 expression and computer-assisted morphometry of digital images to measure the area of pathological changes and CD68 expression. Results: When developing a method for computer-assisted analysis of EMB specimens, we proposed a new evaluation criterion: staining area coefficient (%) that is a ratio of the total stained area to the total section area. We created and field-tested algorithms for digital morphometric analysis to assess the intensity of IHC reactions and to identify the relative area of pathological changes in the EBM specimens. Conclusions: New digital criteria for diagnosing heart transplant rejections are to improve the accuracy of EMB results interpretation, but can also be used for analyzing other biopsy specimens.

Rejection is the primary factor affecting the functionality of a kidney post-transplant, where its prompt prediction of risk significantly influences therapeutic strategies and clinical outcomes. Current graft health assessment methods, including serum creatinine measurements and transplant kidney puncture biopsies, possess considerable limitations. In contrast, urine serves as a direct indicator of the graft's degenerative stage and provides a more accurate measure than peripheral blood analysis, given its non-invasive collection of kidney-specific metabolite. This research entailed collecting fluorescent fingerprint data from 120 urine samples of post-renal transplant patients using hyperspectral imaging, followed by the development of a learning model to detect various forms of immunological rejection. The model successfully identified multiple rejection types with an average diagnostic accuracy of 95.56 %.Beyond proposing an innovative approach for predicting the risk of complications post-kidney transplantation, this study heralds the potential introduction of a non-invasive, rapid, and accurate supplementary method for risk assessment in clinical practice.

T cells serve a pivotal role in the rejection of transplants, both by directly attacking the graft and by recruiting other immune cells, which intensifies the rejection process. Therefore, monitoring T cells becomes crucial for early detection of transplant rejection, while targeted drug delivery specifically to T cells can significantly enhance the effectiveness of rejection therapy. However, regulating the activity of T cells within transplanted organs is challenging, and the prolonged use of immunosuppressive drugs is associated with notable side effects and complications. Functionalized nanoparticles offer a potential solution by targeting T cells within transplants or lymph nodes, thereby reducing the off-target effects and improving the long-term survival of the graft. In this review, we will provide an overview of recent advancements in T cell-targeted imaging molecular probes for diagnosing transplant rejection and the progress of T cell-regulating nanomedicines for treating transplant rejection. Additionally, we will discuss future directions and the challenges in clinical translation.

Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA)-matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2–12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post-infusion, a surrogate measure of cell clearance. Donor cells were cleared by 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01–0.31% of total DNA with no signs of graft-versus-host disease in any participant. The donor DNA clearance times provided by this study have important implications for understanding the safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders. [ABSTRACT FROM AUTHOR]

Background and Objectives: Endobiogeny is a global systems approach to human biology based on the concept that the endocrine system manages the metabolism. Biology of function (BoF) indices are diagnostic tools in endobiogenic medicine that reflect the action of the endocrine system on the cells and the metabolic activity of an organism. Kidney transplant recipients are a very specific patient population due to their constant use of immunosuppressive agents such as steroids and anamnesis of chronic kidney disease. The aim of this study was to assess the tendencies of endobiogenic BoF indices in a kidney transplant recipient population and to determine the relationship between BoF index values and histology-proven kidney transplant rejection. Materials and Methods: A total of 117 kidney transplant recipients undergoing surveillance or indication allograft biopsy were included in this study. Endobiogenic BoF indices were calculated from complete blood count tests taken before the kidney biopsy. Histology samples were evaluated by an experienced pathologist according to the Banff classification system. Clinical and follow-up data were collected from an electronic patient medical record system. Results: Overall, 50% of the patients had lower-than-normal adaptation, leucocyte mobilization, genital, and adjusted genital ratio indices, while the Cata-Ana, genito-thyroid ratio, adrenal gland, and cortisol indices were increased in >50% of the transplant recipients. The adaptation index was significantly higher in patients with biopsy-proven transplant rejection and demonstrated an AUC value of 0.649 (95%CI 0.540–0.759) for discriminating rejectors from patients without transplant rejection. Conclusions: Most of the kidney transplant recipients had abnormal BoF index values, reflecting increased corticotropic effects on their cells. The adaptation index distinguished patients with biopsy-proven transplant rejection from those without it.

Abstract Aim This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). Methods Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. Results A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025: 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. Conclusion Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.

Chronic inflammation contributes to the pathogenesis of many diseases, including apparently unrelated conditions such as metabolic disorders, cardiovascular diseases, neurodegenerative diseases, osteoporosis, and tumors, but the use of conventional anti-inflammatory drugs to treat these diseases is generally not very effective given their adverse effects. In addition, some alternative anti-inflammatory medications, such as many natural compounds, have scarce solubility and stability, which are associated with low bioavailability. Therefore, encapsulation within nanoparticles (NPs) may represent an effective strategy to enhance the pharmacological properties of these bioactive molecules, and poly lactic-co-glycolic acid (PLGA) NPs have been widely used because of their high biocompatibility and biodegradability and possibility to finely tune erosion time, hydrophilic/hydrophobic nature, and mechanical properties by acting on the polymer's composition and preparation technique. Many studies have been focused on the use of PLGA-NPs to deliver immunosuppressive treatments for autoimmune and allergic diseases or to elicit protective immune responses, such as in vaccination and cancer immunotherapy. By contrast, this review is focused on the use of PLGA NPs in preclinical in vivo models of other diseases in which a key role is played by chronic inflammation or unbalance between the protective and reparative phases of inflammation, with a particular focus on intestinal bowel disease; cardiovascular, neurodegenerative, osteoarticular, and ocular diseases; and wound healing. [ABSTRACT FROM AUTHOR]

Immunosuppressive drugs are widely used to prevent rejection after kidney transplantation. However, the pharmacological response to a given immunosuppressant can vary markedly between individuals, with some showing poor treatment responses and/or experiencing serious side effects. There is an unmet need for diagnostic tools that allow clinicians to individually tailor immunosuppressive therapy to a patient's immunological profile. The Immunobiogram (IMBG) is a novel blood-based in vitro diagnostic test that provides a pharmacodynamic readout of the immune response of individual patients to a range of immunosuppressants commonly used in kidney transplant recipients. Here, we discuss the current approaches used to measure the pharmacodynamic responses of individual patients to specific immunosuppressive drugs in vitro, which can then be correlated with patient's clinical outcomes. We also describe the procedure of the IMBG assay, and summarize the results obtained using the IMBG in different kidney transplant populations. Finally, we outline future directions and other novel applications of the IMBG, both in kidney transplant patients and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder's critical quality attributes was explored. The best-performing powder in terms of dissolution time and respirability was obtained starting from a concentration of ethanol of 45% (v/v) in the feedstock solution and 20% (w/w) of mannitol. This powder showed a faster dissolution profile (Weibull dissolution time of 59.5 min) than the poorly soluble raw material (169.0 min). The powder exhibited a fine particle fraction of 66.5% and an MMAD of 2.97 µm. The inhalable powder, when tested on A549 and THP-1, did not show cytotoxic effects up to a concentration of 10 µg/mL. Furthermore, the CsA inhalation powder showed efficiency in reducing IL-6 when tested on A549/THP-1 co-culture. A reduction in the replication of SARS-CoV-2 on Vero E6 cells was observed when the CsA powder was tested adopting the post-infection or simultaneous treatment. This formulation could represent a therapeutic strategy for the prevention of lung rejection, but is also a viable approach for the inhibition of SARS-CoV-2 replication and the COVID-19 pulmonary inflammatory process. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). Methods: Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. Results: A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025: 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. Conclusion: Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs. [ABSTRACT FROM AUTHOR]

Introduction We present a case of urothelial carcinoma in a renal allograft successfully treated with pembrolizumab. Case presentation A 39‐year‐old woman presented with nausea and anorexia 9 years after a renal transplantation. Positron emission tomography revealed a neoplasm of the renal pelvis of the allograft and multiple lymph nodes with peritoneal metastasis. A diagnosis of a non‐muscle‐invasive bladder tumor with peritoneal dissemination and jejunal metastasis of urothelial carcinoma was made. After five cycles of gemcitabine and carboplatin, the tumor progressed and pembrolizumab was administered. One week after the first dose, the allograft was rejected, necessitating arterial embolization. After the second cycle, the patient developed Stevens‐Johnson syndrome. After discontinuing pembrolizumab, positron emission tomography revealed no increased tumor activity. A complete response was achieved for 21 months without additional treatment. Conclusion Pembrolizumab was effective in treating urothelial carcinoma of the renal allograft; however, allograft rejection and loss should be considered.

Abstract Background Immune-inflammatory myocardial disease contributes to multiple chronic cardiac processes, but access to non-invasive screening is limited. We have previously developed a method of echocardiographic texture analysis, called the high-spectrum signal intensity coefficient (HS-SIC) which assesses myocardial microstructure and previously associated with myocardial fibrosis. We aimed to determine whether this echocardiographic texture analysis of cardiac microstructure can identify inflammatory cardiac disease in the clinical setting. Methods We conducted a retrospective case-control study of 318 patients with distinct clinical myocardial pathologies and 20 healthy controls. Populations included myocarditis, atypical chest pain/palpitations, STEMI, severe aortic stenosis, acute COVID infection, amyloidosis, and cardiac transplantation with acute rejection, without current rejection but with prior rejection, and with no history of rejection. We assessed the HS-SIC’s ability to differentiate between a broader diversity of clinical groups and healthy controls. We used Kruskal-Wallis tests to compare HS-SIC values measured in each of the clinical populations with those in the healthy control group and compared HS-SIC values between the subgroups of cardiac transplantation rejection status. Results For the total sample of N = 338, the mean age was 49.6 ± 20.9 years and 50% were women. The mean ± standard error of the mean of HS-SIC were: 0.668 ± 0.074 for controls, 0.552 ± 0.049 for atypical chest pain/palpitations, 0.425 ± 0.058 for myocarditis, 0.881 ± 0.129 for STEMI, 1.116 ± 0.196 for severe aortic stenosis, 0.904 ± 0.116 for acute COVID, and 0.698 ± 0.103 for amyloidosis. Among cardiac transplant recipients, HS-SIC values were 0.478 ± 0.999 for active rejection, 0.594 ± 0.091 for prior rejection, and 1.191 ± 0.442 for never rejection. We observed significant differences in HS-SIC between controls and myocarditis (P = 0.0014), active rejection (P = 0.0076), and atypical chest pain or palpitations (P = 0.0014); as well as between transplant patients with active rejection and those without current or prior rejection (P = 0.031). Conclusions An echocardiographic method can be used to characterize tissue signatures of microstructural changes across a spectrum of cardiac disease including immune-inflammatory conditions.

• A retrospective case series of 25 HCC patients from 3 hospitals who used ICIs prior to LT was reported, and 96 HCC patients were included in literature review. • PD-1 inhibitor monotherapy resulted in significantly higher rejection rate than PD-L1 inhibitor monotherapy and other ICIs combination regimens. • Statistically significant difference was found in immunosuppression regimen between the rejection and non-rejection groups. • The median interval between the last dosage of pembrolizumab and LT was 20 (12–26.5) days in the rejection group and 49.5 (23.5–135) days in the non-rejection group. Studies on the safety of immune checkpoint inhibitors (ICIs) prior to liver transplantation (LT) are still limited to case reports or case series. It is vital to be aware of possible risk of transplant rejection with regards to ICIs after LT. To explore the possible risk of transplant rejection induced by ICIs in hepatocellular carcinoma (HCC) patients and investigate the safe washout interval between ICIs administration and LT. HCC patients from 3 tertiary hospitals in China who received ICIs prior to LT over the past 5 years were analyzed retrospectively. Patients who had experienced transplant rejection were reported in detail. Additionally, a comprehensive search of databases was conducted to identify case reports of HCC patients who underwent LT after receiving ICIs until October 1, 2024. In our study, a total of 25 patients were analyzed. Programmed cell death protein 1 (PD-1) inhibitors were most commonly used (68 %, 17/25). The median interval between the last dose of ICIs and LT was 64 (40–150.75) days. Three patients (12 %) experienced T-cell mediated rejection (TCMR), 1 of which was induced by ICIs, and the other 2 of which could not be excluded from the influence of immunosuppressant concentrations. In literature review, a total of 96 cases of HCC patients who had received ICIs prior to LT were included. PD-1 inhibitor monotherapy resulted in significantly higher rejection than PD-L1 inhibitor monotherapy and other ICIs combination regimens (P = 0.021). In patients with pembrolizumab, the interval from ICIs to LT was shorter in the rejection group than in the non-rejection group (P = 0.045). Twenty-one cases (21.88 %) experienced transplant rejection, and 3 patients passed away following transplant rejection. ICIs prior to LT was associated with the risk of transplant rejection, especially with factors such as the type of ICIs and the interval between ICIs and LT. Multicenter prospective studies are needed to further explore the safety of ICIs. [ABSTRACT FROM AUTHOR]

Patients who undergo solid organ transplantation are at an increased risk of developing atopic dermatitis, potentially due to long‐term use of calcineurin inhibitors which results in a shift towards the Th2 immune response. The effectiveness and safety of dupilumab for atopic dermatitis in posttransplant patients is not established. Previous reports of dupilumab use in posttransplant patients have been in adult patients. In this series, we report three young posttransplant patients treated successfully with dupilumab. [ABSTRACT FROM AUTHOR]

Renal transplantation is currently the best treatment option for patients with end-stage kidney disease. Ischemia/reperfusion injury (IRI), which is an inevitable event during renal transplantation, has a profound impact on the function of transplanted kidneys. It has been well demonstrated that innate immune system plays an important role in the process of renal IRI. As a critical component of innate immune system, Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has received great attention from scientific community over the past decade. The main function of NLRP3 inflammasome is mediating activation of caspase-1 and maturation of interleukin (IL)-1β and IL-18. In this review, we summarize the associated molecular signaling events about NLRP3 inflammasome in renal IRI, and highlight the possibility of targeting NLRP3 inflammasome to minimize renal IRI during transplantation. [ABSTRACT FROM AUTHOR]

Background Macrophages can oscillate between two functionally distinct states: proinflammatory M1 and anti-inflammatory M2. Classically- activated M1 macrophages produce proinflammatory cytokines (TNF-α, IFN-ƴ, and IL-6), which ares associated with graft dysfunction/rejections. In contrast, alternatively-activated macrophages M2 produce anti-inflammatory cytokines (IL-10) that are involved in host defense, tissue repair/remodeling, debris scavenging, and immune regulation, thereby helps to improve long-term graft survival. Methods In this study, we have identified graft dysfunction or rejection by biopsies using immunohistochemistry. Flow cytometry was used to detect M1 (CD163+, CD206+, and CD200R+) and M2 (CD86+, CD80+, and CD68+) macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to measure a panel of cytokines. Results Histological analysis of the kidney transplants (n = 30) was used to distinguish those with acute/chronic allograft rejection (n = 15) from those with stable kidney function (n = 15). Flow cytometry results showed that patients with graft rejection exhibited macrophages with decreased expression (33.28%) of M2 macrophage markers (CD163+, CD206+, and CD200R+) and reduced production of IL-10 (as detected using ELISA). However, 71.33% of the macrophages were found to have M1 markers (CD86+, CD80+, and CD68+; p = 0.002) and produced proinflammatory cytokines (TNF-α, IFN-ƴ, and IL-6) by ELISA (p = 0.001) when compared with the healthy control group. In contrast, stable kidney transplants had 65.58% M2 and 27.66% M1 macrophages (p = 0.03) and produced IL-10. These findings suggest that M1 macrophages dominate in kidney grafts with dysfunction or rejection, whereas M2 macrophages dominate in kidney grafts with stable function. Conclusion Our observations implicate a major shift towards M2 macrophages in stable kidney transplants, which are markedly downregulated in patients with graft dysfunction or rejection. In contrast, an increased frequency of M1 macrophages remained dominant in the pathophysiology of kidney transplants undergoing active dysfunction or rejection. [ABSTRACT FROM AUTHOR]

Background Diagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome. Methods We conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression. Results Clinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001–0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001–0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001–0.499; p = 0.026). Conclusions Our results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

Background: Over the last several decades, the field of lung transplantation has made significant advances. Despite these advancements, morbidity and mortality rates are still high when compared to other solid organ transplants. Clinical trials have a significant role bringing new medications with better effects than their predecessors. Our study is critical in evaluating and tracking clinical trials involving rejection of lung transplant, with a focus on interventional therapeutic trials. Methods: On November 3, 2021, we searched clinicaltrial.gov for interventional clinical trials related to lung transplant rejection. A total of 39 clinical trials are included in this study. Characteristics on each trial were gathered. Linked publications were searched using Medline/PubMed and Embase/Scopus, and their content reviewed and summarized. Results: The majority of trials were divided into completed (15 out of 39) and recruiting (12 out of 39). 17 trials had between 11 and 50 participants, and 8 had above 100. Only 1 trial lasted >10 years, and the average length of all trials was 3.6 years. The majority of trials were conducted in Europe/UK/Russia and the United States/Canada (17 and 18 trials, respectively). The results were provided in 3 trials, and also published in 3, showing a decrease in the rate of patients reaching an endpoint after chronic rejection with liposomal aerosol cyclosporine, a decrease in their cytokines level, and an increase in their 5-year-survival rate compared to the oral conventional immunosuppressant, the benefit of sirolimus in decreasing the acute rejection rate and severity in comparison to azathioprine, and its efficacy against cytomegalovirus infections. Other trials revealed the benefits of azithromycin in remarkably decreasing airways and systemic inflammation, with a concomitant decline in the risk of both BOS and CLAD; highlighting the deleterious effects of air pollution after transplantation surgery; and using the grading biopsy as a post-transplantation assessment tool. Conclusion: This study is a descriptive analysis of clinical trials targeting lung transplant rejection. This study shows the low number of trials, lack of variety in location and low publishing rates. Although focus of published trials was mainly towards azithromycin, bronchiolitis obliterans syndrome, air pollution, and biopsy in grading, a remarkable progress was realized concerning therapies, leading to less complications with a delay of chronic rejection onset, and an increase in overall survival. This sheds the light on the need for managing research efforts to fulfill any lack in specific domain, leading to new, effective therapies, and providing thereby much more benefit. [ABSTRACT FROM AUTHOR]

With over 30,000 patients having received CAR T cells as a treatment for malignancy, our experience in oncology has facilitated numerous efforts to adapt the CAR therapeutic platform for diseases and conditions beyond cancer. Recognition of their efficacy, where traditional small molecule or biologic therapies fail, has spurred multiple efforts leveraging CAR T cells for immune modulation in the setting of organ/tissue transplantation. In the present review, we discuss CAR T cell approaches that are currently under development, to target both humoral and cellular alloimmunity. These include CAR T platforms repurposed from oncology and autoimmune diseases, as well as ones designed specifically to target alloimmunity in transplant. We also present important challenges and application considerations that will need to be addressed before we can expect successful clinical translation. Finally, we highlight a few of the exciting advances currently in development that are likely to pave a smoother path to translating CAR T cell therapies into transplant patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VGB is a co-inventor on a patent related to CAAR technology which is licensed by the University of Pennsylvania to Cabaletta Bio. The remaining authors have no relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme in de novo biosynthesis of purine nucleotides. Due to this important role, it is a great target to drug discovery for a wide range of activities, especially immunosuppressant in heart and kidney transplantation. Both human IMPDH isoforms are expressed in stimulated lymphocytes. In addition to the side effects of existing drugs, previous studies have mainly focused on the type II isoform. In this study, virtual screening and computer-aided approaches were employed to identify potential drugs with simultaneous inhibitory effects on both human IMPDH isoforms. After Re-docking, Double-step docking, and identification of virtual hits based on the PLANTS scoring function, drug-likeness and ADME-Tox assessments of the topmost ligands were performed. Following further evaluation, the best ligand was selected and, in complex with both isoforms, simulated in monomeric and tetrameric forms using molecular dynamics to evaluate its stability and binding pattern. The results showed a potential drug candidate [(S)-N-(3-hydroxy-1-(4-hydroxyphenyl) propyl)-2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide] with a high inhibitory effect on the two human IMPDH isoforms. This drug-like inhibitor could potentially serve as an immunosuppressant to prevent transplant rejection response by inhibiting B- and T-lymphocyte proliferation. In addition, its effect can be evaluated in various therapeutic targets in which IMPDH is known as a therapeutic target, especially in Covid-19 patients.

Long-time ischemia worsening transplant outcomes in vascularized composite allotransplantation (VCA) is often neglected. Ischemia-reperfusion injury (IRI) is an inevitable event that follows reperfusion after a period of cold static storage. The pathophysiological mechanismactivates local inflammation, which is a barrier to allograft long-term immune tolerance. The previous publications have not clearly described the relationship between the tissue damage and ischemia time, nor the rejection grade. In this review, we found that the rejection episodes and rejection grade are usually related to the ischemia time, both in clinical and experimental aspects. Moreover, we summarized the potential therapeutic measures to mitigate the ischemia-reperfusion injury. Compare to static preservation, machine perfusion is a promising method that can keep VCA tissue viability and extend preservation time, which is especially beneficial for the expansion of the donor pool and better MHC-matching. [ABSTRACT FROM AUTHOR]

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNIbased therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break establ i shed immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability. [ABSTRACT FROM AUTHOR]

Abstract Single-cell RNA sequencing (scRNA-seq) is a comprehensive technical tool to analyze intracellular and intercellular interaction data by whole transcriptional profile analysis. Here, we describe the application in biomedical research, focusing on the immune system during organ transplantation and rejection. Unlike conventional transcriptome analysis, this method provides a full map of multiple cell populations in one specific tissue and presents a dynamic and transient unbiased method to explore the progression of allograft dysfunction, starting from the stress response to final graft failure. This promising sequencing technology remarkably improves individualized organ rejection treatment by identifying decisive cellular subgroups and cell-specific interactions.

Long-time ischemia worsening transplant outcomes in vascularized composite allotransplantation (VCA) is often neglected. Ischemia-reperfusion injury (IRI) is an inevitable event that follows reperfusion after a period of cold static storage. The pathophysiological mechanism activates local inflammation, which is a barrier to allograft long-term immune tolerance. The previous publications have not clearly described the relationship between the tissue damage and ischemia time, nor the rejection grade. In this review, we found that the rejection episodes and rejection grade are usually related to the ischemia time, both in clinical and experimental aspects. Moreover, we summarized the potential therapeutic measures to mitigate the ischemia-reperfusion injury. Compare to static preservation, machine perfusion is a promising method that can keep VCA tissue viability and extend preservation time, which is especially beneficial for the expansion of the donor pool and better MHC-matching.

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.