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Fibrosis is a prominent feature of chronic allograft rejection, caused by an excessive production of matrix proteins, including collagen-1. Several cell types produce collagen-1, including mesenchymal fibroblasts and cells of hematopoietic origin. Here, we sought to determine whether tissue-resident donor-derived cells or allograft-infiltrating recipient-derived cells are responsible for allograft fibrosis, and whether hematopoietic cells contribute to collagen production. A fully MHC-mismatched mouse heterotopic heart transplantation model was used, with transient depletion of CD4 + T cells to prevent acute rejection. Collagen-1 was selectively knocked out in recipients or donors. In addition, collagen-1 was specifically deleted in hematopoietic cells. Tissue-resident macrophages were depleted using anti-CSF1R antibody. Allograft fibrosis and inflammation were quantified 20 days post-transplantation. Selective collagen-1 knock-out in recipients or donors showed that tissue-resident cells from donor hearts, but not infiltrating recipient-derived cells, are responsible for production of collagen-1 in allografts. Cell-type-specific knock-out experiments showed that hematopoietic tissue-resident cells in donor hearts substantially contributed to graft fibrosis. Tissue resident macrophages, however, were not responsible for collagen-production, as their deletion worsened allograft fibrosis. Donor-derived cells including those of hematopoietic origin determine allograft fibrosis, making them attractive targets for organ preconditioning to improve long-term transplantation outcomes., 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 © 2022 Balam, Buchtler, Winter, Schmidbauer, Neumayer, Talke, Renner, Geissler and Mack.)

The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (DNGR-1)-dependent cross-presentation of dead-cell-associated antigens occurs after transplantation and contributes to CD8 + T cell responses, chronic allograft rejection (CAR), and fibrosis. BALB/c or C57BL/6 hearts were heterotopically transplanted into WT, Clec9a -/- , or Batf3 -/- recipient C57BL/6 mice. Allografts were analyzed for cell infiltration, CD8 + T cell activation, fibrogenesis, and CAR using immunohistochemistry, Western blot, qRT 2 -PCR, and flow cytometry. Allografts displayed infiltration by recipient DNGR-1 + DCs, signs of CAR, and fibrosis. Allografts in Clec9a -/- recipients showed reduced CAR (p < 0.0001), fibrosis (P = 0.0137), CD8 + cell infiltration (P < 0.0001), and effector cytokine levels compared to WT recipients. Batf3-deficiency greatly reduced DNGR-1 + DC-infiltration, CAR (P < 0.0001), and fibrosis (P = 0.0382). CD8 cells infiltrating allografts of cytochrome C treated recipients, showed reduced production of CD8 effector cytokines (P < 0.05). Further, alloreactive CD8 + T cell response in indirect pathway IFN-γ ELISPOT was reduced in Clec9a -/- recipient mice (P = 0.0283). Blockade of DNGR-1 by antibody, similar to genetic elimination of the receptor, reduced CAR (P = 0.0003), fibrosis (P = 0.0273), infiltration of CD8 + cells (p = 0.0006), and effector cytokine levels. DNGR-1-dependent alloantigen cross-presentation by DNGR-1 + DCs induces alloreactive CD8 + cells that induce CAR and fibrosis. Antibody against DNGR-1 can block this process and prevent CAR and fibrosis., (© 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment., Methods: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232., Findings: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT., Interpretation: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression., Funding: The 7th EU Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity., Methods: Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 weeks after LT (group B, n = 261)., Results: Median MELD at LT was low with 10 (7-15) (group A) and 11 (8-15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (≥stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function., Conclusions: Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.

Background: B-cell-activating factor (BAFF) is associated with donor-specific antibodies (DSA) and poorer outcomes after renal transplantation (RTx). We examined the effects of anti-BAFF treatment on B cells, expression of costimulatory molecules and cytokines, germinal centers (GCs), and DSA formation in an RTx model in rats., Methods: Anti-BAFF antibody was injected on days 3, 17, 31, and 45 after allogeneic RTx. Rats received reduced dose cyclosporine A for 28 or 56 days to allow chronic rejection and DSA formation. Leukocytes, B-cell subsets, and DSA were measured using flow cytometry; expression of cytokines and costimulatory molecules was measured by quantitative polymerase chain reaction, and GCs and T follicular helper were assessed using immunohistochemistry. Rejection was evaluated by a nephropathologist., Results: Anti-BAFF treatment reduced the frequency of B cells in allografts and spleen. Naive B cells were strongly reduced by anti-BAFF treatment in all compartments. Messenger RNA expression of interleukin-6 and the costimulatory molecules CD40 and inducible T cell costimulator ligand was significantly reduced in anti-BAFF-treated rats. GC area was smaller and plasmablasts/plasma cell numbers lower in anti-BAFF-treated rats, which was reflected by less DSA in certain IgG subclasses., Conclusions: Anti-BAFF treatment interferes with humoral responses at multiple levels in this model of allogeneic RTx.

Chronic rejection is a major problem in transplantation medicine, largely resistant to therapy, and poorly understood. We have shown previously that basophil-derived IL-4 contributes to fibrosis and vasculopathy in a model of heart transplantation with depletion of CD4 + T cells. However, it is unknown how basophils are activated in the allografts and whether they play a role when cyclosporin A (CsA) immunosuppression is applied. BALB/c donor hearts were heterotopically transplanted into fully MHC-mismatched C57BL/6 recipients and acute rejection was prevented by depletion of CD4 + T cells or treatment with CsA. We found that IL-3 is significantly upregulated in chronically rejecting allografts and is the major activator of basophils in allografts. Using IL-3-deficient mice and depletion of basophils, we show that IL-3 contributes to allograft fibrosis and organ failure in a basophil-dependent manner. Also, in the model of chronic rejection involving CsA, IL-3 and basophils substantially contribute to organ remodeling, despite the almost complete suppression of IL-4 by CsA. In this study, basophil-derived IL-6 that is resistant to suppression by CsA, was largely responsible for allograft fibrosis and limited transplant survival. Our data show that IL-3 induces allograft fibrosis and chronic rejection of heart transplants, and exerts its profibrotic effects by activation of infiltrating basophils. Blockade of IL-3 or basophil-derived cytokines may provide new strategies to prevent or delay the development of chronic allograft rejection., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Renal impairment and high model of end-stage liver disease scores before liver transplantation (LT) are increasingly common., Patients and Methods: This was a single-arm, 2-step prospective trial of bottom-up calcineurin inhibitor (CNI)-free de novo immunosuppressive treatment (mycofenolate mofetil, steroids, basiliximab) with delayed introduction of sirolimus in patients with renal impairment. Primary endpoint was immunologic safety assessed by the incidence of steroid-resistant rejection within the first 30 days after liver transplantation., Results: Twenty-seven patients were included with a median age of 56 years and labMELD of 28. Baseline glomerular filtration rate was 38 (Cockroft-Gault) and 24 mL/min (modification of diet in renal disease). No steroid-resistant rejections occurred within 30 days. Incidence of biopsy proven acute rejection was 18.5%. Sirolimus was started on day 10 (range, day 1 to day 48). The rate switched to CNI treatment by 1 year was 44%; 1-year overall survival was 93%. Renal function improved significantly, reflected by a Δglomerular filtration rate of 31 mL/min from baseline to 1 year (P = 0.006). Per protocol analysis revealed freedom from CNI, but not presence of sirolimus within the first 30 days, as critical for renal recovery., Conclusions: Initial de novo CNI-free immunosuppressive bottom-up treatment is safe in selected patient groups. The critical period for relevant recovery of renal function seems to be the early period (first 30 days), independent from presence of sirolimus.

By exploiting mechanisms of immunological regulation against donor alloantigen, it may be possible to reduce the dependence of kidney transplant recipients upon calcineurin inhibitor-based maintenance immunosuppression. One means to strengthen regulatory responses is treating recipients with preparations of regulatory cells obtained by ex vivo manipulation. This strategy, which is a well-established experimental method, has been developed to the point that early-phase clinical trials in kidney transplantation are now feasible. Cell-based therapies represent a radical departure from conventional treatment, so what grounds are there for this new approach? This article offers a three-part justification for trialing cell-based therapies in kidney transplantation: first, a clinical need for alternatives to standard immunosuppression is identified, based on the inadequacies of calcineurin inhibitor-based regimens in preventing late allograft loss; second, a mechanistic explanation of how cell-based therapies might address this clinical need is given; and third, the possible benefit to patients is weighed against the potential risks of cell-based immunosuppressive therapy. It is concluded that the safety of cell-based immunosuppressive therapy will not be greatly improved by further basic scientific and preclinical development. Only trials in humans can now tell us whether cell-based therapy is likely to benefit kidney transplant recipients, but these should be conservative in design to minimize any potential harm to patients.

Background: Natural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets., Methods: Because T-bet controls thematuration of NK cells from CD27high to terminally differentiated CD27low NK cells, we used Rag−/−T-bet−/− mice that lackmature CD27low NK cells to study the distinct roles of CD27low versus CD27high NK cells in a model of Tcell–mediated skin transplant rejection under costimulatory blockade conditions., Results: We found that T cell–reconstituted Rag1−/− recipients (possessing CD27low NK cells) show significantly prolonged allograft survival on costimulatory blockade when compared to Rag1−/−T-bet−/− mice (lacking CD27low NK cells), indicating that CD27low but not CD27high NK cells enhance allograft survival. Critically, Rag1−/−T-bet−/− recipients showed strikingly increased alloreactive memory CD8+ Tcell responses, as indicated by increased CD8+ Tcell proliferation and interferon-γ production. Therefore, we speculated that CD27low NK cells directly regulate alloreactive CD8+ Tcell responses under costimulatory blockade conditions. To test this, we adoptively transferred CD27low NK cells into Rag1−/−T-bet−/− skin transplant recipients and found that the CD27low NK cells restore better allograft survival by inhibiting the proliferation of alloreactive interferon-γ+CD8+ T cells., Conclusions: In summary, mature CD27low NK cells promote allograft survival under costimulatory blockade conditions by regulating alloreactive memory CD8+ T-cell responses.

Although Th1, Th2, and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. To precisely address this, we used mice genetically modified for the Th1 and Th17 hallmark transcription factors T-bet and RORγt, respectively, which allowed us to study the alloreactive role of each subset in an experimental transplant setting. We found that in a fully mismatched heterotopic mouse heart transplantation model, T cells deficient for T-bet (prone to Th17 differentiation) versus RORγt (prone to Th1 differentiation) rejected allografts at a more accelerated rate, indicating a predominance of Th17- over Th1-driven alloimmunity. Importantly, T cells doubly deficient for both T-bet and RORγt differentiated into alloreactive GATA-3-expressing Th2 cells, which promptly induced allograft rejection characterized by a Th2-type intragraft expression profile and eosinophilic infiltration. Mechanistically, Th2-mediated allograft rejection was contingent on IL-4, as its neutralization significantly prolonged allograft survival by reducing intragraft expression of Th2 effector molecules and eosinophilic allograft infiltration. Moreover, under IL-4 neutralizing conditions, alloreactive double-deficient T cells upregulated Eomesodermin (Eomes) and IFN-γ, but not GATA-3. Thus, in the absence of T-bet and RORγt, Eomes may salvage Th1-mediated alloimmunity that underlies IL-4 neutralization-resistant allograft rejection. We summarize that, whereas Th17 cells predictably promote allograft rejection, IL-4-producing GATA-3(+) Th2 cells, which are generally thought to protect allogeneic transplants, may actually be potent facilitators of organ transplant rejection in the absence of T-bet and RORγt. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and RORγt.

Purpose of Review: To consolidate our basic scientific and technological appreciation of human regulatory macrophages (M reg) as a cell-based medicinal product for use as an adjunct immunosuppressive therapy in organ transplantation., Recent Findings: Building on the original observation that crude preparations of IFN-γ-stimulated allogeneic macrophages prolong allograft survival in experimental animals, we have arrived at a detailed understanding of the derivation, phenotype and T-cell-suppressive potential of a population of in-vitro-derived human macrophages, which have been designated M regs. This basic scientific knowledge has inspired methodological advances in M reg manufacture, leading to a purer and more homogeneous cell product. In turn, cells produced by these improved protocols have been applied in the clinic, so completing a cycle of technological development. Studying the migration and physiological impact of M reg administration in patients provides a measure of reassurance that the procedure is well tolerated. Cutting-edge strategies to assess the immunological status of solid organ transplant recipients allow the biological effects of M reg treatment to be monitored., Summary: A view of the human M reg as a novel, stringently defined medicinal product is presented, opening exciting possibilities for its future investigation as a therapy in solid organ transplantation and beyond.

Regulatory macrophages (M regs) were administered to two living-donor renal transplant recipients. Both patients were minimized to low-dose tacrolimus monotherapy within 24 wk of transplantation and subsequently maintained excellent graft function. After central venous administration, most M regs remained viable and were seen to traffic from the pulmonary vasculature via the blood to liver, spleen, and bone marrow. By 1 y posttransplantation, both patients displayed patterns of peripheral blood gene expression converging upon the IOT-RISET signature. Furthermore, both patients maintained levels of peripheral blood FOXP3 and TOAG-1 mRNA expression within the range consistent with nonrejection. It is concluded that M regs warrant further study as a potential immune-conditioning therapy for use in solid-organ transplantation. The results of this work are being used to inform the design of The ONE Study, a multinational clinical trial of immunomodulatory cell therapy in renal transplantation.

Use of the mammalian target of rapamycin (mTOR) inhibitor rapamycin in organ transplantation has evolved through different phases over the past two decades. After its discovery in the mid 1970s, antifungal and cytotoxic effects were the first of its properties to be explored, but the most significant advancement was found in its use as an immunosuppressive agent to reduce transplant rejection. This was viewed as an important step forward for immunosuppression, as early studies suggested that rapamycin was less nephrotoxic than calcineurin inhibitors (CNIs). Later, detrimental effects of rapamycin on kidney function were found in some patients. Nonetheless, a fascination with the mTOR pathway and its central role in multiple cellular processes has ensued. Among the potential positive clinically relevant effects is rapamycin's capacity to interfere with fibrotic processes that often accompany transplant rejection, and to influence the preferential development of immunological tolerance. A feature of increasing importance is that the mTOR pathway is central for vital aspects of tumor development, including angiogenesis and cell growth; rapamycin, therefore, has anticancer activities, which may prove critical in the fight against high cancer rates in transplant recipients. The final chapters defining the value of rapamycin have not been written yet, and indeed remain a work in progress. Only further research will reveal the full potential of rapamycin in organ transplantation.

Cancer is an increasingly recognized problem associated with immunosuppression. Recent reports, however, suggest that the immunosuppressive agent rapamycin has anti-cancer properties that could address this problem. Thus far, rapamycin's effects on immunity and cancer have been studied separately. Here we tested the effects of rapamycin, versus cyclosporine A (CsA), on established tumors in mice simultaneously bearing a heart allograft. In one tumor-transplant model, BALB/c mice received subcutaneous syngenic CT26 colon adenocarcinoma cells 7 days before C3H ear-heart transplantation. Rapamycin or CsA treatment was initiated with transplantation. In a second model system, a B16 melanoma was established in C57BL/6 mice that received a primary vascularized C3H heart allograft. In vitro angiogenic effects of rapamycin and CsA were tested in an aortic ring assay. Results show that CT26 tumors grew for 2 weeks before tumor complications occurred. However, rapamycin protected allografts, inhibited tumor growth, and permitted animal survival. In contrast, CsA-treated mice succumbed to advancing tumors, albeit with a functioning allograft. Rapamycin's antitumor effect also functioned in severe combined immunodeficient BALB/c mice. Similar effects of the drugs occurred with B16 melanomas and primary vascularized C3H allografts in C57BL/6 mice. Furthermore, in this model, rapamycin inhibited the tumor growth-enhancing effects of CsA. Moreover, in vitro experiments showed that CsA promotes angiogenesis by a transforming growth factor-beta-related mechanism, and that this effect is abrogated by rapamycin. This study demonstrates that rapamycin simultaneously protects allografts from rejection and attacks tumors in a complex transplant-tumor situation. Notably, CsA protects allografts from rejection, but cancer progression is promoted in transplant recipients.

Paclitaxel is an anti-neoplastic drug that was recently shown also to have immunosuppressive properties in naïve rat heart transplant recipients. Here, we tested whether paclitaxel could also effectively reverse an ongoing immune response in transplant recipients. We therefore used a model in which Lewis rat recipients receiving ACI rat heterotopic heart allografts were: (1) untreated, or treated with either (2) paclitaxel or (3) cyclosporine, starting 5 days after transplantation. Allograft survival was determined in one group, and in a second group cytotoxic T-lymphocyte (CTL) responses were determined and serum anti-donor cytotoxic antibody levels were measured. Results showed that paclitaxel was as effective as cyclosporine in saving recipients from imminent allograft rejection. Immunologically, paclitaxel reduced the allogeneic-CTL response, but most impressively, the cytotoxic antibody response was nearly eliminated in saved recipients. Therefore, paclitaxel's immunosuppressive properties, along with its known effectiveness against a wide variety of tumors, makes it potentially useful for the simultaneous treatment of rejection and neoplasms in cases of transplant-related cancer.

Sensitized organ transplant recipients face an increased risk of hyperacute rejection (HAR) due to donor major histocompatibility complex (MHC) class I antigen (Ag) preexposure. We recently reported a novel donor-specific strategy to address this problem, whereby soluble donor MHC class I Ag gene therapy prevented HAR of heart allografts in passively sensitized rats. Here, we tested this same approach in presensitized rat recipients with a fully preactivated humoral and cellular immune response. Our gene therapy method involved liposomal transfection of cultured recipient (Lewis-RT1.A(1)) hepatocytes with DNA encoding secretable donor MHC class I Ag, RT1.A(a). Control-transfected or RT1.A(a)-transfected hepatocytes were implanted intrasplenically into Lewis rats presensitized with three skin transplants. Subsequently, antidonor antibody, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) assays were performed. Additionally, the effectiveness of our gene therapy on the prevention of ACI (RT1(a)) heart HAR was evaluated. Results indicated that soluble MHC not only decreased cytotoxic antibody levels, but also suppressed antidonor CTL and HTL responses; furthermore, HAR of heart allografts was prevented in all recipients. Therefore, soluble donor MHC class I gene therapy can inhibit multiple aspects of the primed antidonor immune response in actively presensitized rats. Development of this strategy in presensitized humans could improve organ transplant outcome.

Clinical studies with cellular therapies using tolerance-inducing cells, such as tolerogenic antigen-presenting cells (tolAPC) and regulatory T cells (Treg) for the prevention of transplant rejection and the treatment of autoimmune diseases have been expanding the last decade. In this perspective, we will summarize the current perspectives of the clinical application of both tolAPC and Treg, and will address future directions and the importance of immunomonitoring in clinical studies that will result in progress in the field. [ABSTRACT FROM AUTHOR]

Summary Interleukin-33 (IL-33) stimulates the generation of cells and cytokines characteristic of a Th2 immune response. We examined the effects of IL-33 on allografted heart tissue in a chronic cardiac rejection model, including analysis of the peripheral myeloid and lymphoid compartments. B6.C-H2bm12/KhEg hearts were transplanted into MHC class II-mismatched C57Bl/6J mice; IL-33 was administered daily. Cells from allografts and spleens were isolated for flow cytometry and cultured for cytokine production; some tissues were used for immunohistochemistry. Animals treated with IL-33 showed significantly longer allograft survival, which was associated with a distinct cytokine profile produced by graft-infiltrating cells. Proinflammatory IL-17A production was decreased with IL-33 treatment, while increased levels of IL-5, IL-10, and IL-13 were observed. After IL-33 therapy, flow cytometry showed a direct induction of CD4+ Foxp3+ Treg, whereas the number of B220+ CD19+ B cells, and circulating, as well as allograft deposited, alloantibodies was reduced. Following IL-33 treatment, a significant decrease in graft-infiltrating CD11bhighGr1high granulocytes coincided with a significant increase in CD11bhighGr1intermediate myeloid-derived suppressor cells (MDSC). In conclusion, IL-33 treatment in the setting of chronic rejection promotes the development of a Th2-type immune response that favors MDSC and Treg expansion, reduces antibody-mediated rejection (AMR), and ultimately, prolongs allograft survival. [ABSTRACT FROM AUTHOR]

This report describes the case of patient FR, a 31-year-old recipient of a living-related kidney transplant from a donor against whom he was presensitized. Seventeen days prior to transplantation, a central venous infusion of transplant acceptance-inducing cells (TAICs) was administered to the patient. During the 27-month follow up, the patient experienced no acute rejection episodes under an immunosuppressive regime comprising anti-thymocyte globulin (ATG) induction, corticosteroids and tacrolimus. In a similar manner to the kidney transplant recipients treated preoperatively with TAICs in a previous study, patient FR achieved a state of donor-specific hypo-responsiveness. Most remarkably, the deliberate preoperative exposure of a sensitized patient to the sensitizing alloantigen did not heighten his response; on the contrary, after TAIC treatment and transplantation, HLA-specific antibodies were no longer detectable. The case of patient FR provides further evidence of the safety of pre-transplantation treatment with TAICs. [ABSTRACT FROM AUTHOR]

The article discusses graft dysfunction in kidney transplant recipients and notes antibody mediated rejection (AMR) as the leading cause. It discusses an experiment involving administering belimumab to kidney transplant recipients who were receiving standard immunosuppressors for treatment of AMR. Preliminary results of drug trials indicate low risks of infection and T-cell-mediated rejection and suggest that this can be effective in treatment of AMR.

Background: The liver is an immunological organ containing a large number of T, NK and NKT cells, but little is known about intrahepatic immunity after LTx. Here, we investigated whether the distribution of T, NK and CD3+CD56+NKT cells is altered in transplanted livers under different circumstances. Methods: Core biopsies of transplanted livers were stained with antibodies against CD3 and CD56. Several cell populations including T (CD3+CD56-), NK (CD3+CD56+) and NKT cells (CD3+CD56+) were studied by fluorescence microscopy. Cell numbers were analyzed in relation to the time interval after LTx, immunosuppressive therapy and stage of acute graft rejection (measured with the rejection activity index: RAI) compared to tumor free liver tissue from patients after liver resection due to metastatic disease as control. Results: Recruitment of CD3+CD56+NKT cells revealed a significant decrease during high RAI scores in comparison to low and middle RAI scores (RAI 7-9:0.03±0.01/HPF vs. RAI 4-6:0.1-4- 0.005/HPF). CD3+CD56+NKT cells were also lower during immunosuppressive therapy with tacrolimus (0.03±0.01/HPF) than with cyclosporine (0.1±0.003/HPF), cydosporine/MMF (0.1±0.003/HPF) or simlimus (0.1±0.01/HPF) treatment. Intrahepatic T cell numbers increased significantly 50 days after LTx compared to control liver tissue (4.5±0.2/HPF vs. 1.9±0.1/HPF). In contrast, NK cells (0.3±0.004/HPF) were significantly fewer in all biopsies after LTx compared to the control (0.7±0.04/HPF). Conclusions: These data indicate significant alterations in the hepatic recruitment of T, NK and CD3+CD56+NKT cells after LTx. The increase in T cells and the decrease in NK and CD3+CD56+NKT cells suggest a shift from innate to adaptive hepatic immunity in the liver graft. [ABSTRACT FROM AUTHOR]