Immunoregulatory role of chimerism in clinical organ transplantation

FoxP3 mRNA Transcripts and Regulatory Cells in Renal Transplant Recipients 10 Years After Donor Marrow Infusion

“…In this light as well, the functional in vitro effects we have previously demonstrated of extracted bone marrow cell subpopulations in patients given such infusions (2-4, 31, 32), although not performed here because of a lack of donor cell samples, may be attributed to an increase of T-regs elicited by the chimeric bone marrow, eliciting an increase in FoxP3-producing PBL T cells. Somewhat similar, but functional, findings in vitro were recently reported by Velthuis et al (40) in a series of living donor kidney transplant recipients (non-DBMC infused), and similar to our reports previously (2)(3)(4). As such, the real in vivo functional effect might be considered to be improved long-term graft survival in the DD DBMC-infused recipient group reported on here vs. the demographically and otherwise equivalently treated noninfused controls (1).…”

“…In a series of earlier reports, we also demonstrated the ex vivo function of immunoregulatory cells present, especially in the chimeric bone marrow of recipients having been infused with either living-related or DD DBMC in the peritransplant period (2)(3)(4). However, with a few exceptions (5-7), a favorable clinical response elicited by DBMC infusions has been open to question.…”

“…It might be speculated that these other cells may be more expansile or contractile in response to (allo)antigen and immunosuppression and, as mentioned, perhaps are also induced by iDC after contact with (putative) higher DC2:DC1 ratios (commensurate with that seen in this report in the bone marrow of NLs). This speculatively might have occurred on a continuing basis in the DBMC-infused chimeric recipient marrows, such as regulatory DBMC effects previously described (2)(3)(4), where such T cell to chimeric (donor) iDC contact would have been amplified upon recipient T cell recirculation through the marrow compartment in which chimerism was 10-fold higher than in peripheral blood (43). Despite not depicting FoxP3 protein by antibody studies in the present report, mRNA copies of FoxP3 has been an acceptable way of reporting this phenomenon (24,25,34,44).…”

Five-year clinical effects of donor bone marrow cells infusions in kidney allograft recipients

“…10 Long-term follow up of these patients revealed more favorable ten year graft survival, higher levels of chimerism in iliac crest marrow samples, increased expression of Foxp3 mRNA, and in vivo function of immunoregulatory cells in peripheral blood lymphocytes in DBMC-infused patients. [15][16][17][18] Similar observations were made in clinical trials by several groups describing long-term acceptance of kidney or liver allografts even after immunosuppression withdrawal. [19][20][21][22] The current report describes the five-year follow up of a series of 20 living unrelated donor (LURD) kidney allograft recipients between March 2005 and July 2007, who were given donor bone marrow cells infusion and prospectively followed.…”

Microchimerism in promoting graft acceptance in clinical transplantation

“…It might be speculated that regulation by donor chimeric cells may also involve the induction of anergy [76] possibly by incomplete antigen presentation in the absence of costimulatory molecules [84], tolerogenic allopeptides [85] or by the transduction of an as yet undefined negative signal, perhaps even involving B cells [86, 87] with a memory and inhibitory phenotype [88]. Prolonged and sustained regulation or anergy may eventually lead to the clonal deletion, thereby bringing about classical immunologic tolerance [89]. …”