Cyclosporine Facilitates Chimeric and Inhibits Nonchimeric Tolerance After Posttransplant Total Lymphoid Irradiation1

Abstract

Cyclosporine facilitated long-term graft acceptance in a tolerization protocol that induced mixed chimerism, but prevented long-term graft acceptance in a tolerization protocol that did not induce chimerism.

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

“…This regimen has been used successfully to induce tolerance to vascularized heart allografts in rats and to kidney allografts in humans (7,13,14). Unexpectedly, the removal of the anti-T cell Abs from the regimen in the current study resulted in uniform heart graft rejection with uniform mixed chimerism.…”

“…This posttransplant-conditioning regimen consisting of total lymphoid irradiation (TLI) 3 and anti-thymocyte globulin has been previously shown to induce mixed chimerism and tolerance to vascularized heart grafts in completely MHCmismatched rats (13,14). A key advantage of the posttransplant regimen is that it can be applied to human cadaver organ transplantation.…”

“…Because the timing of the availability of cadaver organs cannot be predicted or planned, pretransplant-conditioning regimens cannot be used in the clinical setting. In addition, tolerance induction using the TLI and anti-thymocyte globulin regimen is facilitated by the use of the calcineurin inhibitor, cyclosporine, a frequently used immunosuppressive drug in clinical organ transplantation (14).…”

“…To achieve long-term cardiac tissue allograft acceptance and mixed chimerism using BALB/c (H-2 d ) host and C57BL/6 (H-2 b ) donor mice, we conditioned hosts with a nonmyeloblative posttransplantation regimen of fractionated irradiation of the spleen, lymph nodes, and thymus with marrow shielding (TLI), depletive anti-T cell Abs, and an infusion of donor bone marrow cells that had been reported to tolerize MHC-mismatched rats (13,14). Host mice received neonatal donor heart allografts transplanted to the ear pinnae on day 0, 5 doses of ATS i.p.…”

Radiotherapy and Immunity – A Mini Review

“…Conditioning regimens used to achieve mixed chimerism and tolerance include lethal and sublethal total body irradiation (TBI) with or without thymic irradiation and anti-T cell antibodies (Ildstad & Sachs 1984;Kawai et al, 2002;Stykes 2001), www.intechopen.com TLI with and without anti-T cell antibodies (Slavin et al, 1976;Slavin et al, 1978;Slavin et al, 1977;Scandling et al, 2008 ;Hayamizu et al, 1999;Lan et al, 2000;Higuchi et al, 2002), costimulatory blockade with or without rapamycin therapy or cytoreduction (Wekerle et al, 2000;Durhan et al, 2000;Lambert et al, 2002;Graca et al, 2006), injection of naturally occurring CD4+CD25+ Treg (nTreg) cells combined with radiation cytoreduction (Golshayn et al, 2007;Wood & Sakaguchi, 2003), and chemical cytoreduction combined with thymic irradiation, and anti-T cell antibodies (Fudaba et al, 2006;Kawai et al 2008,). Although central and peripheral clonal deletion in chimeras can explain the lack of reactivity of host immune cells to donor alloantigens (Stikes 2001;Wekerle et al, 1998), host regulatory T cells that remain after cytoreduction or that are injected after cytoreduction can also play an important role in the engraftment of the donor organ and hematopoietic cells (Higushi 2002, Golshayn et al, 2007Wood & Sakaguchi 2003).…”