Donor and recipient leukocytes in organ allografts of recipients with variable donor-specific tolerance: With particular reference to chronic rejection

Abstract

We have attributed organ engraftment to clonal exhaustion-deletion of host-versus-graft and graft-versus-host reactions that are reciprocally induced and governed by migratory donor and recipient leukocytes. The so-called donor passenger leukocytes that migrate from the allograft into the recipients have been thoroughly studied (chimerism), but not the donor leukocytes that remain in, or return to, the transplanted organ. Therefore, using flow cytometry we determined the percentage and lineages of donor leukocytes in cell suspensions prepared from Lewis (LEW) cardiac allografts to 100 days posttransplantation. The LEW hearts were transplanted to naïve untreated Brown Norway (BN) recipients (group 2), to naïve BN recipients treated with a 28-day or continuous course of tacrolimus (TAC) (groups 3 and 4), and to drug-free BN recipients pretolerized by earlier bone marrow cell (BMC) or orthotopic LEW liver transplantation (groups 5 and 6). The findings in the heart cell suspensions were correlated with the results from parallel histopathologic-immunocytochemical studies and other studies of the grafts and of host tissues. Although the LEW heart allografts were rejected in 9.6 days by the unmodified recipients of group 2, all beat for 100 days in the recipients of groups 3 through 6. Nevertheless, all of the long-surviving cardiac allografts (but not the isografts in group 1) were the targets of an immune reaction at 5 days, reflected by dramatic increases in the ratio of leukocytes to nonleukocyte nucleated cells from normal values of 1:5-1:6 to 1:1-5:1 and by manifold other evidence of a major inflammatory event. The acute changes returned to baseline by 100 days in the chronic rejection (CR) free hearts of groups 4 and 6, but not in the CR-afflicted hearts of short-course TAC group 3 or the less-severely damaged hearts of the BMC-prime group 5.The freedom from CR in groups 4 and 6 was associated with a large donor contribution to the intracardiac leukocyte population at 5 days (28.6% and 22% in the respective groups) and at 100 days (30.5% in group 4 and 8.4% in group 6) compared with 2% and 1.2% at 100 days in the CR-blighted allografts of the partially tolerant animals of groups 3 and 5. Whether large or small, the donor leukocyte fraction always included a subset of class II leukocytes that had histopathologic features of dendritic cells. These class II ؉ cells were of mixed myeloid (CD11-b/c ؉ ) and lymphoid lineages; their migration was markedly inhibited by TAC and accelerated by donor-specific priming and TAC discontinuance. Although a large donor leukocyte population and a normal leukocyte/nonleukocyte cell ratio were associated with freedom from CR, these findings and the lineage profile of the intracardiac leukocytes were not associated with tolerance in the animals of groups 3 and 4 under active TAC treatment. The findings in this study, singly and in their entirety, are compatible with our previously proposed leukocyte migration-localization paradigm of organ allograft acceptance and tolerance. (Liver ...

Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance

“…Allostimulatory APC have been demonstrated to give rise to Treg in other model systems (50). Cardiac allografts have previously been shown to possess passenger DC (51). However, in our model system, Tol-DC were of recipient origin, as they possessed BALB/c (H-2 d ), but not C57BL/6 (H-2 b ) MHC class II.…”

Tolerance for organ recipients: A clash of paradigms

“…14,15,17,18 It follows that the completeness of tolerance short of the drug-free state can be inferred from the amount of immunosuppression needed to maintain graft stability. 18,24,25 None of the patients of Donckier et al 1 had macrochimerism. But the first 2 recipients clearly achieved a high degree of drug-free tolerance that can be considered with certainty to be microchimerism dependent.…”

Identification of patients best suited for combined liver[ndash ]kidney transplantation: Part II

“…83 Last, it is possible that passenger leukocytes within the liver result in greater microchi- merism than after kidney-only transplantation, with the subsequent development of tolerance. [84][85][86] Unfortunately, lower early renal allograft rejection rates have not always translated into improved renal graft survival, in part because of increased patient death after liver compared with kidney-only transplantation (Fig. 4).…”