Chimerism and Donor-Specific Nonreactivity 27 to 29 Years After Kidney Allotransplantation

Abstract

Chimerism was demonstrated with immunocytochemical and/or polymerase chain reaction techniques in kidney allografts and in the native skin, lymph nodes, or blood of 5 of 5 patients who received continuously functioning renal transplants from 1 or 2 haplotype HLA mismatched consanguineous donors (4 parents, 1 aunt) 27-29 years ago. In the 4 cases where the kidney donor still was alive to provide stimulator lymphocytes for testing, these provoked no (n = 2) or modest (n = 2) MLR in contrast to vigorous MLR to third party lymphocytes. In all 4 cases, the donor cells failed to generate in vitro cytotoxic effector cells (cell-mediated lymphocytotoxicity). These findings are in accord with the hypothesis that cell migration, repopulation, and chimerism are seminal events that define graft acceptance and ultimately can lead to acquired donor-specific nonresponsiveness (tolerance).

Bone Marrow Augmentation in Renal Transplant Recipients

“…Although we believe that microchimerism is a requirement for long-term organ allograft acceptance, 1,2,26,27 there are limitations to the chimerism-inducing strategies. Recipient hematolymphopoietic cytoreduction or cytoablation unquestionably enhances the ease and extent of donor leukocyte engraftment, but the potential penalty with each further increment in cytoreduction is proportionate weakening of the biologic safety device (against GVHD and rejection) that is provided by the nullification effect of the dual cell populations, 34 as has been learned with conventional bone marrow allotransplantation.…”

“…1,2,26 These findings led to the development of the two-way paradigm to explain the immunologic relationship between the donor and the recipient 1,2,27 and ultimately to the Starzl/Zinkernagel explanation of acquired immunologic tolerance. 3 At the beginning, the simplistic therapeutic assumption was that if microchimerism was essential for long-term graft survival, the long-term prognosis, including achievement of drugfree tolerance, might be improved by augmenting the spontaneous chimerism with perioperative donor bone marrow.…”

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

“…For the first time, it was speculated in 1991 that graft chimerism might be a generic feature of all accepted grafts (13). This speculation soon was demonstrated with the kidney (14) and thoracic organs (15)(16)(17).…”

The lost chord: microchimerism and allograft survival

“…However, five of the ten longestsurviving patients bearing living-related kidney allografts have been completely off immunosuppression for between three and 30 years (Table 2). Patients 3 and 4, whose mixed lymphocyte response (MLR) tests to donor and third party targets were profoundly depressed prior to weaning 44 , had gradual restoration of MLR to both in the drug-free state, but with no evidence of rejection.…”