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Achieving Solid Organ Transplant Tolerance: New Findings, More Questions and the Search Continues

Maluf, Daniel G. MD1; Leventhal, Joseph R. MD2; Mas, Valeria R. PhD1

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doi: 10.1097/TP.0000000000003264
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Tolerance, the specific absence of a harmful alloimmune response to a graft tissue in the absence of immunosuppression, is the main step for successful complete immunosuppressive drug withdrawal following solid organ transplantation.1 The two most explored tolerance applications to solid organ transplantation are operational tolerance and deletional tolerance. Operational tolerance refers to stable graft function off immunosuppression for at least 1 year in the absence of chimerism.1 However, it has been described that a very limited number of all recipients of renal transplants have maintained stable renal function after discontinuing immunosuppressant therapy.2 Deletional tolerance refers to the type of tolerance described by Owen3 and Billingham et al.4 Based on these initial observations made over half a century ago,3,4 the establishment of hematopoietic cell chimerism has been thought to be the pathway to transplant tolerance. In clinical kidney transplantation, the primary method used to achieve tolerance has been transplantation of hematopoietic cells in combination with transplantation of the kidney from the same donor. With this approach, tolerance and successful immunosuppressive drug withdrawal have been accomplished in living donor transplantation, in HLA-matched and in HLA-mismatched donor/recipient pairs.5

Induction of tolerance to liver transplants is an area of active research. The liver microenvironment is inherently programmed towards induction of tolerance as a result of evolution to avoid immune activation on exposure to the gut delivered antigens.6 This has imperative implications for alloimmunity in the context of liver transplantation alone or in multivisceral transplants. It is well recognized that the liver is an immunologically privileged organ, compared with other organs that are commonly transplanted. The liver allograft not only protects itself from the host immune system, but this protection also extends to other simultaneously transplanted solid organs from the same donor.6

In this issue of Transplantation, the report by Chaudhry et al7 describes the results of a cynomolgus monkey model of simultaneous liver and donor bone marrow transplant performed with the aim of inducing tolerance early after liver transplantation. Based on described tolerogenic characteristics of the liver, the authors hypothesized that tolerance to liver transplants would occur at least as often as was reported for the kidney. Contrarily, results showed that livers were rejected rapidly after immunosuppression withdrawal. Analysis of the mechanism of rejection revealed a correlation between peripheral and intra-graft expansion of effector-memory CD8 T cells and graft loss. The findings support that induction of transient mixed hematopoietic chimerism induced by nonmyeloablative conditioning does not promote tolerance in liver transplantation using the cynomolgus monkey liver transplant model.

These results are intriguing despite the study’s limitations including a small sample size and high posttransplant mortality. As described by the authors, the small group size used mainly reflects the difficulty of performing liver transplants in a macaque model and the need to make modifications of early protocols to reduce morbidity/mortality and achieve better clinical outcomes. Strategies which were well tolerated when transplanting other organs—namely kidneys—needed to be adjusted to safely achieve the final goal of transient donor chimerism. In fact, surgical factors related to complexity of the liver transplant procedure may have impacted the study, not only by affecting survival of animals but also by influencing the tolerogenic ability of the liver. Specifically, the liver graft is being exposed to more drastic surgical damage and ischemic injury than kidneys, which may result in a sweeping pro-inflammatory environment. Moreover, in the cynomolgus model, other investigators have reported that induction of tolerance following combined organ and bone marrow transplants is highly dependent on which solid organ is co-transplanted with the bone marrow.8

Additionally, severe acute cellular rejection was observed soon after withdrawal of immunosuppression. The authors suggest that the identification of peripheral and intra-graft expansion of effector-memory CD8 T cells and graft loss represents a major barrier to tolerance induction in this model. Kim et al9 reported using an allogeneic ABO compatible liver transplant model in rhesus monkeys that memory T cells were drastically increased in livers with rejection. Likewise, several studies have shown that alloreactive memory T cells are a major barrier to the induction of tolerance in kidney and islet allografts. The report by Chaudhry et al7 therefore confirms the observations of others regarding the potential importance of memory CD8+ T cells as a barrier to tolerance induction. Larger, carefully designed mechanistic studies are needed to better elucidate the role of this cell population, and the results of targeting these effector cells a way forward to the induction of tolerance. Interesting, although using a rat liver transplant model, Xie et al10 reported that T cell-depleted bone marrow infusion is effective in inducing tolerance when delayed after liver transplantation. Furthermore, organ-specific modifications of the protocols of tolerance induction maybe necessary.

Finally, as supported by other publications and discussed by the authors, a possible role of the kidney in the induction of transplantation tolerance needs to be taken into consideration. This point warrants further evaluation in future studies.

In closing, although critical advances have been made in the tolerance field with successful trials ongoing in living donor kidney transplant patients, multiple questions remain unanswered. The current study by Chaudhry et al,7 from one of the few centers in the world using the described model, represents an additional piece of information supporting that the complexity associated with tolerance induction and the need to develop organ-specific models and protocols.

REFERENCES

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2. Orlando G, Hematti P, Stratta RJ, et al. Clinical operational tolerance after renal transplantation: current status and future challenges. Ann Surg. 2010; 252:915–928
3. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945; 102:400–401
4. Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Phil Trans R Soc Lond B. 1956; 239:357–414
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7. Chaudhry S, Kato Y, Weiner J, et al. Transient mixed chimerism with nonmyeloablative conditioning does not induce liverallograft tolerance in nonhuman primates. Transplantation[Epub ahead of print. April 6, 2020] doi: 10.1097/TP.0000000000003263
8. Sasaki H, Oura T, Spitzer TR, et al. Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach. Hum Immunol. 2018; 79:258–265
9. Kim H, Kim H, Lee SK, et al. Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys. Liver Transpl. 2018; 24:256–268
10. Xie Y, Wu Y, Xin K, et al. Delayed donor bone marrow infusion induces liver transplant tolerance. Transplantation. 2017; 101:1056–1066
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