Chimerism and tolerance in transplantation

Abstract

Studies in experimental models (1953)(1954)(1955)(1956)) demonstrated that acquired donor-specific allotolerance in immunologically immature or irradiated animals is strongly associated with donor leukocyte chimerism. Bone marrow transplantation in immune-deficient or cytoablated human recipients was a logical extension (1968). In contrast, clinical (1959) and then experimental organ transplantation was systematically accomplished in the apparent absence of leukocyte chimerism. Consequently, it was assumed for many years that success with organ and bone marrow transplantation involved fundamentally different mechanisms. With the discovery in 1992 of small numbers of donor leukocytes in the tissues or blood of long-surviving organ recipients (microchimerism), we concluded that organ engraftment was a form of leukocyte chimerismdependent partial tolerance. In this initially controversial paradigm, alloengraftment after both kinds of transplantation is the product of a double immune reaction in which responses, each to the other, of coexisting donor and recipient immune systems results in variable reciprocal clonal exhaustion, followed by peripheral clonal deletion. It was proposed with Rolf Zinkernagel that the individual alloresponses are the equivalent of the MHC-restricted T cell recognition of, and host response to, intracellular parasites and that the mechanisms of immune responsiveness, or nonresponsiveness, are governed by the migration and localization of the respective antigens. Elucidation of the mechanisms of nonresponsiveness (clonal exhaustion-deletion and immune ignorance) and their regulation removed much of the historical mystique of transplantation. The insight was then applied to improve the timing and dosage of immunosuppression of current human transplant recipients.

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

“…3,4 This phenomenon may be a prerequisite for the maintenance of induced clonal deletion, a critical mechanism for acquired tolerance following transplantation. [5][6][7] Since the pioneering study by Starzl et al evaluating persistent systemic microchimerism in long-term allograft recipients, many clinical trials have been performed to confirm whether DBMC infusion can promote donor specific hyporesponsiveness thus improving long-term allograft survival. 4 However, only a limited number of trails (8)(9)(10)(11)(12) showed specific hyporesponsiveness and improved allograft survival in DBMC infused recipients compared with non-infused transplant recipients.…”

Partial HLA matching and RH incompatibility resulting in graft versus host reaction and Evans syndrome after liver transplantation

“…Chimerism and engraftment appeared restricted to the CD2 1 compartment. In the past, investigators have attempted to create donor microchimerism as a way to elicit long term immune tolerance [7]. The enthusiasm for this approach has largely waned.…”

Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

“…Donor lymphocyte chimerism post organ transplant may change with time elapsed transplant [22]. Chimerism, the coexisting of donor and recipient immune system [23], could have complicated the investigation in post liver transplant recipients.…”