On minor histocompatibility antigens, mixed chimerism, and transplantation tolerance (2020)

The article from Mahr et al. on page 968 clarifies the contributions of major and minor histocompatibility antigens to the induction of mixed chimerism and allograft tolerance when using a clinically relevant noncytoreductive regimen. The article from Mahr et al. on page 968 clarifies the contributions of major and minor histocompatibility antigens to the induction of mixed chimerism and allograft tolerance when using a clinically relevant noncytoreductive regimen. The mechanisms through which allografts are rejected are mostly determined by how proinflammatory T cells recognize donor antigens, which varies depending on the immunological status of the recipient, the type allograft, its vascularization and anatomical location. Recipient alloreactive T cells can recognize donor alloantigens as intact donor allogeneic major histocompatibility complex (MHC) molecules presented by donor antigen presenting cells (APCs) (the direct allorecognition pathway), as intact donor allo-MHC molecules acquired by recipient APCs (the semidirect pathway), or as donor-derived peptides loaded onto self-MHC molecules expressed by self-APCs. The latter mechanism, known as the indirect allorecognition pathway, elicits immune responses that can target either peptides derived from allo-MHC molecules or non-MHC immunogenic polymorphic molecules referred to as minor histocompatibility antigens (miHA). Although with yet poorly defined mechanisms, the capacity of miHA mistmaches to elicit allograft rejection is well recognized. This is illustrated in humans by the development of kidney allograft rejection in human leucocyte antigen (HLA)-identical donor-recipient sibling combinations (with the exception of identical twins). However, the clinical setting in which miHA-induced alloimmunity has been most extensively studied is HLA-matched allogeneic hemopoietic stem cell transplantation (HSCT). The donor-recipient miHA mismatch is a key determinant for accomplishing the graft-versus-leukaemia (GvL) effect but also for the development of graft-versus-host disease (GvHD). Allogeneic HSCT has been employed to create hematopoietic chimeras and induce tolerance to solid organ transplants. Although this is the only successful strategy for inducing kidney allograft tolerance in humans,1Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (850) Google Scholar its clinical applicability is largely limited by the reliance on toxic cytoreductive conditioning regimens and the risk of GvHD. Work conducted in preclinical animal models indicates that immunological tolerance could result either from the complete replacement of the recipient immune system with the donor one (full chimeras), or from the selective central (thymic) deletion of recipient alloreactive T cells (mixed chimeras). However, observations in HLA-mismatched kidney transplant recipients that transient mixed chimerism can be sufficient to ensure indefinite graft survival have suggested that,1Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (850) Google Scholar in humans, immunoregulatory mechanisms are likely to play a role in the long-term protection of the allograft. The relevance of nondeletional peripheral mechanisms such as regulatory T cells (Tregs) became apparent especially when using low-intensity conditioning regimens.2Domenig C Sanchez-Fueyo A Kurtz J et al.Roles of deletion and regulation in creating mixed chimerism and allograft tolerance using a nonlymphoablative irradiation-free protocol.J Immunol. 2005; 175: 51-60Crossref PubMed Scopus (67) Google Scholar Donor-specific Tregs are recruited during the homeostatic reconstitution that promotes donor hematopoietic engraftment even in the absence of high doses of HSCs. However, the achievement of stable hematopoietic chimerism does not seem sufficient to the indefinite survival of same donor skin allografts, which suffer chronic rejection in the form of gradual graft attrition.3Luo B Chan W Shapiro A et al.Non-myeloablative mixed chimerism approaches and tolerance, a split decision.Eur J Immunol. 2007; 37: 1233-1242Crossref PubMed Scopus (23) Google Scholar This state of split tolerance has been proposed to be the consequence of alloimmunity directed against skin-specific miHAs not expressed by the HSCs.3Luo B Chan W Shapiro A et al.Non-myeloablative mixed chimerism approaches and tolerance, a split decision.Eur J Immunol. 2007; 37: 1233-1242Crossref PubMed Scopus (23) Google Scholar Similarly, there is evidence that some miHAs selectively elicit a GvL rather than a GvH effect. The article from Mahr et al4Mahr B, Pilat N, Granofszky N, et al. Distinct roles for major and minor antigen barriers in chimerism-based tolerance under irradiation-free conditions [published online ahead of print July 6, 2020]. Am J Transplant. https://doi.org/10.1111/ajt.16177.Google Scholar in the current issue of the American Journal of Transplantation dissects the exact contributions of MHC and miHA to the induction of mixed chimerism and allograft tolerance in a Balb/C into C57BL/6 model, using a clinically relevant regimen combining co-stimulation blockade and rapamycin without total body irradiation. In this model, complete MHC mismatch constituted an unsurmountable barrier to bone marrow transplant (BMT) engraftment unless recipient NK cells were depleted. Even then, donor-type skin allografts were rejected in all recipients despite persistent levels of mixed chimerism. In contrast, both BMT engraftment and skin allograft tolerance were established in NK-depleted recipients when using complete MHC-mismatched but miHA-matched donors. Consistently, BMT from MHC-matched but miHA-mismatched donors engrafted without the need for NK depletion but did not induce tolerance to the same donor skin allografts. From a therapeutic standpoint the challenge is to identify strategies to overcome the miHA barrier to allograft tolerance induction. In this regard, the same research group described in a previous report5Pilat N Mahr B Unger L et al.Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization.JCI Insight. 2016; 1 (e85911.)Crossref PubMed Scopus (13) Google Scholar that the administration of recipient-type Tregs at the time of BMT effectively controlled skin allograft miHA-driven alloimmunity by eliciting an infectious tolerance process and promoting Treg intragraft accumulation. These results provide the rationale for clinical trials currently in preparation exploring the addition of Treg immunotherapy to mixed chimerism inducing regimens. However, they also raise the question of why costimulation blockade plus rapamycin, shown to expand and strengthen the endogenous Treg compartment across a variety of different models, fails to do so in mixed chimerism recipients. Hematopoietic chimerism constitutes the most robust approach currently available to induce allograft tolerance in clinical transplantation. In order for this strategy to become a realistic alternative to lifelong pharmacological immunosuppression, however, minimally toxic nonmyeloablative conditioning regimens will be required. Far from being an academic curiosity, the work outlined here indicates that these regimens fail to induce tolerance to allograft-specific miHA, thus bearing fundamental implications that beg for additional research into the mechanisms through which miHA-driven alloimmunity is regulated. Many questions remain to be addressed: How are indirectly presented peptides derived from donor MHC, but not miHA, effectively tolerized in completely mismatched strain combinations? Why do recipient skin-specific miHA fail to induce GvHD in mixed chimeric recipients? Are these findings generalizable to allografts other than skin? Overall, the question of why and how HSC are much more tolerogenic than cells from any other organ remains unanswered. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.