Abstract
The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient’s immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.
Highlights
T cell reactions to organ allografts are directed largely to major histocompatibility (MHC) antigens expressed on donor cells, both within the graft and on graft-resident leucocytes; these “passenger leucocytes” migrate from the graft to the periphery to activate host T cells [1]
We examined the effects of irradiating skin allografts to deplete antigen-presenting cells (APC) and T cells before transplantation [18], followed by IL-2cplx treatment of the host to promote host T regulatory cells (Tregs) entry into the grafts
Several groups demonstrated increased survival of mismatched organs depleted of graft-resident cells in rodent models [5,6,7,8], there is contrary evidence suggesting beneficial immunomodulatory effects of passenger leucocytes in transplantation [17]
Summary
T cell reactions to organ allografts are directed largely to major histocompatibility (MHC) antigens expressed on donor cells, both within the graft and on graft-resident leucocytes; these “passenger leucocytes” migrate from the graft to the periphery to activate host T cells [1]. T cells make “indirect” contact with donor antigens as the result of degradation of their MHC molecules into specific donor peptides that bind to host MHC molecules displayed on host APC Both direct and indirect pathways of allorecognition are involved in graft rejection, the relative importance of these two pathways is still controversial [3]. Thereafter, it was shown that graft immunogenicity can be attenuated by reduction of passenger leucocytes, via either prior organ culture in vitro or pre-transplantation on host-type mice With both approaches, depletion of passenger leucocytes retarded rejection and prolonged survival of skin allografts in rodent models [5, 6]. Studies of heart allograft transplantation in rats showed prolongation of survival if donor and/or organ were pretreated with a combination of photochemicals, total body irradiation (TBI) and injection of antilymphocyte globulin [7, 8]
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