In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10).

Abstract

Transplantation between genetically disparate individuals requires chemotherapeutic agents to suppress the rejection reaction. Although these agents are vital to the suppression of graft rejection, they have their own deleterious side effects caused by both nonspecific immunosuppression and drug toxicities. In addition, chronic rejection in varying degrees of severity often occurs despite the use of these agents.Since Medawar and colleagues (1) reported the induction of specific transplantation tolerance in mice by neonatal injection of allogeneic bone marrow cells, the search for methods to induce specific tolerance in adult recipients has continued (2-5). We have recently shown (6) that reconstitution of lethally irradiated B 10 mice with T cell-depleted syngeneic (B 10) plus xenogeneic (F344 rat) bone marrow results in long-term survival of animals without apparent graft vs. host or wasting disease and leads to specific prolongation of donor-type, fullthickness tail skin grafts. Such animals promptly rejected third party allogeneic and xenogeneic skin grafts with a time course similar to that of unirradiated control animals.Our hypothesis for explaining these preliminary results was that syngeneic components offered immunocompetence, while xenogeneic elements led to hyporeactivity across a species barrier. However, neither the extent or specificity of this phenomenon as assessed by in vivo and in vitro parameters nor the nature of T cell responsiveness had been characterized in these animals. In this paper, we present data detailing the extent and specificity of hyporeactivity achieved across a species barrier. Mixed reconstituted animals are shown to exhibit specific hyporeactivity to donor antigens as assessed by skin grafting and by in vitro assays, including mixed lymphocyte culture proliferative and cellular cytotoxicity. These animals were immunocompetent, as evidenced by rejection of third party mouse and rat skin grafts and development of anti-sheep red blood cell plaqueforming responses equivalent to those of syngeneic controls. This new approach offers a model for investigation of mechanisms of self-recognition and induction and maintenance of transplantation tolerance across species barriers.

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…Given the genetic diversity of the human population, allelic tissue-specific antigens in islets or other tissues may be expected to provide targets for rejection in chimeric recipients. In addition, because polymorphisms probably play a critical role in many cases of split tolerance, one can anticipate that split tolerance will be particularly frequent in chimerism approaches to xenotransplantation [18,[56][57][58]. Bone marrow transplantation and treatment protocols BALB/c bone marrow cells were prepared by flushing the femur and tibia with PBS followed by passage of cell suspensions through a nylon mesh.…”

Variable Chimerism, Graft-Versus-Host Disease, and Tolerance After Different Kinds of Cell and Whole Organ Transplantation From Lewis to Brown Norway Rats

“…The parabiotic animals were mixed chimeras, mimicking the effects of placental cross-circulation described by Owen in freemartin cattle (49), that included the acceptance of reciprocal skin grafts (50). The findings of Martinez, Shapiro, and Good (48) defined a principle that presaged the GVHD resistance of mixed chimerism in the total-lymphoid irradiation models of Slavin and Strober (51,52) and the experiments ofTIdstad and Sachs (53)(54)(55)(56). A more recent analogy to the archival parabiotic experiments has been provided by the mouse orthotopic hepatic transplant model of Qian et al (4) in which the liver allograft, which is spontaneously accepted with most strain combinations, has had the uncanny resemblance of a tolerogenic parabiotic partner to its chimeric and reciprocally tolerogenic recipient.…”

Variable Chimerism, Graft-Versus-Host Disease, and Tolerance After Different Kinds of Cell and Whole Organ Transplantation From Lewis to Brown Norway Rats

“…The parabiotic animals were mixed chimeras, mimicking the effects of placental crosscirculation described by Owen in freemartin cattle (49), that included the acceptance of reciprocal skin grafts (50). The findings of Martinez, Shapiro, and Good (48) defined a principle that presaged the GVHD resistance of mixed chimerism in the total-lymphoid irradiation models of Slavin and Strober (51,52) and the experiments of Ildstad and Sachs (53)(54)(55)(56). A more recent analogy to the archival parabiotic experiments has been provided by the mouse orthotopic hepatic transplant model of Qian et al (4) in which the liver allograft, which is spontaneously accepted with most strain combinations, has had the uncanny resemblance of a tolerogenic parabiotic partner to its chimeric and reciprocally tolerogenic recipient.…”