Tolerance induction following allogeneic vascularized bone marrow transplantation - the possible role of microchimerism

Abstract

We have noticed that bone marrow transplanted in a vascularized limb graft, providing a continuous supply of donor bone marrow cells (BMC), may prolong the survival time of a skin graft from the same donor. The question arises whether the microchimerism raised plays a role in the prolonged survival of skin allografts. The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMTx) concomitantly with the rejection process of transplanted skin. Brown Norway (BN) rats served as donors and Lewis rats as recipients of VBMTx and free skin flap allografts. A hind limb was transplanted, followed by a full-thickness skin graft on the dorsum. Cellular microchimerism was investigated in recipients of VBMTx and skin grafts in blood, spleen, mesenteric lymph node, and bone marrow with the monoclonal antibody OX27 directed against MHC class I polymorphic RT1 on BN cells and quantitatively analyzed in a FACStar. In the VBMTx group, the free skin flap survived 70 days after weaning off cyclosporine A (CsA). An intravenous infusion of BMC in suspension equivalent to that grafted in the hind limb did not prolong skin graft survival after cessation of CsA therapy. Donor-derived cells could be detected in VBMTx recipients as long 70 days after weaning off CsA but not in recipients of i.v. suspension BMC grafting.

Combined Anti‐CD154/CTLA4Ig Costimulation Blockade‐Based Therapy Induces Donor‐Specific Tolerance to Vascularized Osteomyocutaneous Allografts

“…Although the exact mechanism for the failure of the protocol in those animals has yet to be determined, we were able to show that the remaining 12 tolerant animals in this group had a significantly lower percentage of CD4 + and CD8 + T cells and higher numbers of CD4 + CD25 + Foxp3 + cells in peripheral blood compared with the three recipients that rejected. This is in line with previous demonstrations of an inverse relationship between CD8 + T cells and Tregs that appears to promote allograft survival with different regimens in various models . Similarly, Wekerle et al showed early (1 week after BM transplantation) deletion of peripheral donor‐reactive host CD4 + T cells, demonstrating a role for peripheral clonal deletion of donor‐reactive T cells in the presence of CoB .…”

The intragraft vascularized bone marrow component plays a critical role in tolerance induction after reconstructive transplantation

“…In VBM, the natural stromal microenvironment of BM cells is preserved. [17][18][19] The stromal microenvironment or niche provides trophic support for cell proliferation and may play an important regulatory role in lymphocyte function and transplant immunology. [20][21][22] Compared to intravenous donor BM cell infusion, VBM has been shown to facilitate donor cell expansion in the BM cavities of lethally irradiated rats.…”