Costimulation blockade (CoB) regimens are a promising immunomodulatory strategy to prevent transplant rejection. However, their efficacy is affected by multiple factors, including still unknown ones. Recently, a couple of reports have highlighted the unexpected capacity of passenger donor lymphocytes to limit the efficacy of tolerogenic therapies: they can enhance the recipient's anti-graft response. Further studies are then necessary to understand their role in different settings of regulation of alloreactivity. In this study we aimed to assess if T lymphocytes contained in the donor specific transfusion (DST) inoculum, used as part of a very effective CoB regimen, contribute to the observed limited regulation of skin transplant rejection.

A peri-transplant regimen based on the administration of total splenocytes as DST+anti-CD154 (MR-1) has a profound protective effect on mouse skin allotransplantation. However, it does not induce long term survival (MST=58 days). When T cells were depleted from the splenocytes used as DST, the beneficial effect was statistically increased (MST=105 days). We studied the specific role of CD4 and CD8 T cell of the inoculum by addition of two groups that received DST with depletion of CD4 or CD8 T cells respectively. Surprisingly, the absence of CD8 T lymphocytes induced a remarkable improvement in transplant survival, with 65% of the grafts surviving beyond 180 days. On the contrary, the absence of CD4 abrogated the prolongation of survival observed with the total-T cell depletion in the DST, bringing survival back to a value, MST=64, comparable to that of unmanipulated DST. In ongoing experiments, we are aiming to determine what correlation exists between the presence/absence/type of donor T lymphocytes and the levels of donor specific antibodies, generation of autoantibodies, or variations in the strength of the direct and indirect alloresponses.

Overall, these data reveal the existence of a novel and very important opposing role for donor passenger lymphocytes regarding their contribution to the modulation of recipient's alloimmunity that significantly modifies the efficacy of DST+MR1 based regimens: a deleterious role for donor CD8, and a beneficial one for CD4 T cells. Identification of the specific mechanisms through which these divergent modulations of the anti-donor alloresponse are exerted will be pivotal for the optimization of clinically effective tolerogenic therapies.

CITATION INFORMATION: Iglesias M., Chicco M., Lee W., Brandacher G., Raimondi G. Donor T Cells Undermine the Graft-Protective Effect of DST Plus Anti-CD154 Am J Transplant. 2017;17 (suppl 3).

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