Induced regulatory T cells in allograft tolerance via transient mixed chimerism

Abstract

Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+ T cell responses in tolerant (TOL) recipients, while marked CD4+ T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+ cells were FOXP3+ in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+ cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.

Chimerism-based tolerance in organ transplantation: preclinical and clinical studies

“…Furthermore, the expansion of T regs in tolerant recipients was inhibited by blocking transforming growth factor (TGF)-b, which resulted in restoration of antidonor CD8 1 T cell responses. These observations suggest that specific loss of anti-donor CD8 1 T cell responses are maintained by donor-specific induced T regs [25]. We also found that T regs were enriched significantly in the kidney allograft of tolerant recipients.…”

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…Similarly, marked enrichment of FOXP3-expressing Tregs during the early post-transplant course has been observed following the non-myeloablative anti-CD2 mAb-based CKHCT protocol that leads to transient chimerism [31, 66]. Consistently, a recent study suggested donor-specific FOXP3+ Treg expansion in tolerant NHPs receiving a T cell depletion/costimulatory blockade-based transient chimerism CKHCT regimen [67]. Mouse models have decisively established a causal link between accumulations of donor-reactive FOXP3+ Tregs and transplant tolerance through a variety of experimental approaches, including targeted deletion of FOXP3-expressing Tregs, which disrupted well-established tolerance [68, 69].…”

Advances in the immunology of heart transplantation

“…5–8 Of note, recent data support the hypothesis that specific induction of Tregs by donor antigens plays a key role in tolerance induced by transient mixed chimerism in non-human primate recipients of kidney, lung and heart allografts (see later). 9 …”