IL35 Production After Living-donor Renal Transplantation: Relevance to Local, Exosome-mediated, Clinical Tolerance

We previously reported that 100% of HLA-identical siblings and 50% of HLA-haploidentical donor-recipient pairs exhibited bidirectional immunoregulation (BDIR) before living-related renal transplantation. BDIR predicted successful transplant outcomes. However, at the time, we were unaware of the role of the cytokine interleukin-35 (IL35) in immunoregulation, and we now appreciate exosomes as a means of confining immunoregulation to the transplanted tissue. Here we show that HLA-identical sibling transplants use IL35 in posttransplant BDIR.

We analyzed the posttransplant IL35 response using the trans-vivo delayed type hypersensitivity assay in HLA-identical sibling transplants, using anti-IL35 antibodies to block immune-regulatory function as measured by either (1) inhibition of the tetanus toxoid/diphtheria toxoid recall response or (2) uncovering of direct response, in both the donor anti-recipient and the recipient anti-donor (minor H) antigen directions.

We found that minor antigen-specific human regulatory T cells, known to be present in peripheral blood mononuclear cell of HLA-identical siblings pretransplant, also caused BDIR via production of IL35 posttransplant.

We conclude that human IL35 is a component of BDIR in HLA-identical sibling transplantation. Since IL35 is one of a subclass of exosome-delivered cytokines, this means that human IL35 could sustain local BDIR within the transplant itself. It follows that local BDIR would persist indefinitely if donor leukocytes were allowed to stably engraft. This may account for the success of combined total lymphoid irradiation/bone marrow transplantation/renal transplantation induction of stable tolerance in HLA-identical sibling transplant recipients.