Increasing Donor Chimerism and Inducing Tolerance to Islet Allografts by Post-Transplant Donor Lymphocyte Infusion

Abstract

Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

Development of Either Split Tolerance or Robust Tolerance along with Humoral Tolerance to Donor and Third-Party Alloantigens in Nonmyeloablative Mixed Chimeras

“…However, although islet-specific autoimmunity could lead to donor islet rejection by chimeras, as suggested in a previous study (32), the lack of syngeneic islet rejection in our study indicated that autoimmunity could not explain the split tolerance. The remaining low-level alloreactivity to the donor, detected in NOD chimeras, could instead explain their increased split tolerance as compared with B6 chimeras.…”

“…The strain combinations used in these studies in most cases were not fully mismatched, having either partial (31,32,44,45) or complete MHC matches (46). Difficulty in sustaining mixed chimerism long term was encountered even in studies that used partially matched donor bone marrow (32,44). However, in one study, fully mismatched islets were accepted by diabetic NOD mice made chimeric, although full chimerism may have explained the tolerance (43).…”

“…1D and 3C and our unpublished observations). Given these and other data (32), it seems likely that the threshold level of chimerism required to prevent islet rejection is increased in the autoimmune-prone NOD background.…”

“…Many studies reported the ability of chimerism induction to promote long-term islet acceptance in NOD mice that already manifested autoimmune diabetes (31, 32, 41, 43-46). The strain combinations used in these studies in most cases were not fully mismatched, having either partial (31,32,44,45) or complete MHC matches (46). Difficulty in sustaining mixed chimerism long term was encountered even in studies that used partially matched donor bone marrow (32,44).…”

Endogenous Expansion of Regulatory T Cells Leads to Long-Term Islet Graft Survival in Diabetic NOD Mice

“…The induction of tolerance to islet antigens via treatment with hematopoietic lineage cells has been reported in a variety of model systems (39)(40)(41). In other model systems, these cell transfers have been thought to result in changes in antigen presentation that preferentially engage tolerance and suppressive mechanisms on APC subsets and naïve and effector T-cell subsets.…”