Sequential transplantation of the liver-kidney-heart from different donors: a case report.

Background: Multi-organ transplantation has emerged as a viable treatment strategy for patients afflicted with multiple organ failure or significant organ dysfunctions. Despite the promising therapeutic outcomes, this approach also amplifies the risk of organ rejection, infection, or neoplastic growth. We present a unique case of a patient who sequentially underwent liver, kidney, and heart transplantation, all sourced from different donors. This case brings forth intriguing possibilities about the interplay between cardiovascular diseases and complications arising post-transplantation, thereby enriching our understanding of comprehensive transplant immunomodulation and cardiovascular disease prevention. Case summary: A 59-year-old male with chronic alcohol misuse developed liver cirrhosis in 2012 and subsequent kidney failure in 2018 due to alcoholic liver disease, type II diabetes, hyperlipidaemia, and severe hypertension. Subsequently, an incident of extensive transmural myocardial infarction (Killip III) warranted a heart transplant in 2022. Post-transplant, the patient was maintained on a standard immunosuppression regimen with regular post-operative follow-ups. No signs of rejection were noted 1-year post-final transplantation under standard immunosuppression. Discussion: The presented case exemplifies the potential and feasibility of sequential multi-organ transplantation. The multifaceted interplay between the transplanted organs and the immunosuppressive pharmaceuticals likely exert distinct influences on transplantation immune regulation, possibly diverging from the dynamics observed in single-organ transplantation. A comprehensive exploration of the mechanisms governing immune responses in the context of multi-organ transplantation could yield valuable insights for mitigating graft dysfunction. Furthermore, the rapid progression of atherosclerosis observed after liver and kidney transplantation necessitates further scrutiny to elucidate potential correlations with the post-transplantation state.

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

The interleukin (IL)-6/IL-6 receptor-α (IL-6Rα)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti-human IL-6Rα blockade by tocilizumab (TCZ) has been used in pig-to-baboon organ xenotransplant models, but whether it is beneficial remains uncertain. After xenotransplant, there were significant increases in both baboon and pig IL-6 in the baboon serum, especially in baboons that received TCZ before xenotransplant. In vitro observations demonstrated that human, baboon, and pig IL-6 can activate the IL-6/IL-6Rα/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL-6/IL-6Rα/STAT3 pathway was blocked by TCZ in human and baboon cells but not in pig cells (ie, pig IL-6R). Siltuximab (human IL-6 inhibitor) bound to both human and baboon, but not pig, IL-6 and suppressed activation of the IL-6/IL-6Rα/STAT3 pathway. These results indicate that TCZ and siltuximab do not cross-react with pig IL-6R and pig IL-6, respectively. Rapamycin partially inhibited human, baboon, and pig IL-6/IL-6Rα/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL-6 because it could no longer bind to baboon IL-6Rα. We suggest that increased serum IL-6 may be detrimental to the pig xenograft because it is likely to bind to pig IL-6R, resulting in activation of pig cells.

Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens.

BACKGROUND: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. METHODS: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. RESULTS: The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. CONCLUSIONS: Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.

Data on B cell phenotypes in baboons with pig artery patch grafts receiving conventional immunosuppressive therapy.

This report is related to the research article entitled "B cell phenotypes in baboons with pig artery patch grafts receiving conventional immunosuppressive therapy" (Yamamoto et al., in press). Herein we provide the data regarding pig artery patch xenotransplantation into the baboon׳s aorta, trough levels of tacrolimus and rapamycin in the blood after transplantation, analysis of B cell phenotype on the basis of IgD and CD27 expression in the blood, and analysis of T cell phenotype on the basis of CD28 and CD95 expression in the blood.

B cell phenotypes in baboons with pig artery patch grafts receiving conventional immunosuppressive therapy.

BACKGROUND: In the pig-to-baboon artery patch model with no immunosuppressive therapy, a graft from an α1,3-galactosyltransferase gene-knockout (GTKO) pig elicits a significant anti-nonGal IgG response, indicating sensitization to the graft. A costimulation blockade-based regimen, e.g., anti-CD154mAb or anti-CD40mAb, prevents sensitization. However, neither of these agents is currently FDA-approved. The aim of the present study was to determine the efficacy of FDA-approved agents on the T and B cell responses. METHODS: Artery patch xenotransplantation in baboons was carried out using GTKO/CD46 pigs with (n = 2) or without (n = 1) the mutant transgene for CIITA-knockdown. Immunosuppressive therapy consisted of induction with ATG and anti-CD20mAb, and maintenance with different combinations of CTLA4-Ig, tacrolimus, and rapamycin. In addition, all 3 baboons received daily corticosteroids, the IL-6R blocker, tocilizumab, at regular intervals, and the TNF-α blocker, etanercept, for the first 2 weeks. Recipient blood was monitored for anti-nonGal antibody levels by flow cytometry (using GTKO/CD46 pig aortic endothelial cells), and mixed lymphocyte reaction (MLR). CD22+B cell profiles (naïve [IgD+/CD27-], non-switched memory [IgD+/CD27+], and switched memory [IgD-/CD27+] B cell subsets) were measured by flow cytometry. At 6 months, the baboons were euthanized and the grafts were examined histologically. RESULTS: No elicited anti-pig antibodies developed in any baboon. The frequency of naïve memory B cells increased significantly (from 34% to 90%, p = 0.0015), but there was a significant decrease in switched memory B cells (from 17% to 0.5%, p = 0.015). MLR showed no increase in the proliferative T cell response in those baboons that had received CTLA4-Ig (n = 2). Histological examination showed few or no features of rejection in any graft. CONCLUSIONS: The data suggest that immunosuppressive therapy with only FDA-approved agents may be adequate to prevent an adaptive immune response to a genetically-engineered pig graft, particularly if CTLA4-Ig is included in the regimen, in part because the development of donor-specific memory B cells is inhibited.

Overcoming Coagulation Dysregulation in Pig Solid Organ Transplantation in Nonhuman Primates: Recent Progress.

There has recently been considerable progress in the results of pig organ transplantation in nonhuman primates, largely associated with the availability of (i) pigs genetically engineered to overcome coagulation dysregulation, and (ii) novel immunosuppressive agents. The barriers of thrombotic microangiopathy and/or consumptive coagulation were believed to be associated with (i) activation of the graft vascular endothelial cells by a low level of antipig antibody binding and/or complement deposition and/or innate immune cell activity, and (ii) molecular incompatibilities between the nonhuman primate and pig coagulation-anticoagulation systems. The introduction of a human coagulation-regulatory transgene, for example, thrombomodulin, endothelial protein C receptor, into the pig vascular endothelial cells has contributed to preventing a procoagulant state from developing, resulting in a considerable increase in graft survival. In the heterotopic (non-life-supporting) heart transplant model, graft survival has increased from a maximum of 179 days in 2005 to 945 days. After life-supporting kidney transplantation, survival has been extended from 90 days in 2004 to 499 days. In view of the more complex coagulation dysfunction seen after pig liver and, particularly, lung transplantation, progress has been less dramatic, but the maximum survival of a pig liver has been increased from 7 days in 2010 to 29 days, and of a pig lung from 4 days in 2007 to 9 days. There is a realistic prospect that the transplantation of a kidney or heart, in combination with a conventional immunosuppressive regimen, will enable long-term recipient survival.