Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance.

Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts

Islet xenografts in fully xenogeneic (rat----mouse) chimeras: evidence for normal regulation of function in a xenogeneic mouse environment.

BACKGROUND: Transplantation of untreated rat bone marrow into mouse recipients conditioned by total-body irradiation results in fully xenogeneic chimerism (rat----mouse). The chimerism is stable for up to 10 months, survival is excellent, and there is no evidence for graft-versus-host disease. We recently reported the long-term survival (greater than 180 days) of donor-specific pancreatic islet xenografts in these fully xenogeneic chimeras. METHODS: Chimeras were prepared and typed for chimerism at 6 weeks, and diabetes was induced by streptozocin injection. Donor-specific pancreatic islets were placed under the renal capsule and recipient blood glucose levels were followed biweekly. The aim of this study was to examine whether the transplanted pancreatic islets exhibited normal function in a xenogeneic environment and assess whether the islet xenografts were not only sufficient to support euglycemia but also regulated in function in response to a glucose challenge. RESULTS: We report for the first time that donor-specific rat islet xenografts were capable of producing normal basal and peak levels of insulin and responding to a glucose challenge in a manner similar to that of normal mouse islets. CONCLUSIONS: These data indicate that donor-specific rat islet xenografts are functional and regulated normally in fully xenogeneic (rat----mouse) chimeras

Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (F344 rat to B10 mouse)

We recently reported that reconstitution of lethally irradiated BIO mouse recipients with 40x10s untreated WF rat bone marrow cells resulted in stable fully xenogeneic chimerism (WF rat → B10 mouse). In these animals, the tolerance induced for skin xenografts was highly MHC specific in that donor-specific WF rat skin grafts were significantly prolonged while MHC-dispar-ate third-party xenografts were rapidly rejected (median survival time [MST] = 9 days). We have now examined whether islet cell xenografts placed under the renal capsule of chimeras rendered diabetic with strep-tozotocin would be accepted and remain functional to maintain euglycemia. Animals were prepared, typed for chimerism at 6 weeks, and diabetes induced with strep-tozotocin. Donor-specific WF (RtlA") islet cell xenografts were significantly prolonged (MST >180 days) in WF → B10 chimeras, while MHC-disparate third-party F344 rat (RtlA1) grafts were rejected with a time course similar to unmanipulated BIO mice (MST=8 days). The transplanted donor-specific islet cells were functional to maintain euglycemia, since removal of the grafts at from 100 to 180 days in selected individual chimeras uniformly resulted in return of the diabetic state. These data suggest that donor-specific islet cell xenografts are accepted and remain functional in mice rendered tolerant to rat xenoantigens following bone marrow transplantation. © 1992 by Williams and Wilkins

Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic graft-versus-host disease occurrence.

International audienceBACKGROUND: Use of a reduced-intensity conditioning regimen before an allogeneic hematopoietic cell transplantation is frequently associated with an early state of mixed hematopoietic chimerism. Such a coexistence of both host and donor hematopoietic cells may influence posttransplant alloreactivity and may affect the occurrence and severity of acute and chronic graft-versus-host disease (GVHD) as well as the intensity of the graft-versus-leukemia effect. Here we evaluated the relation between chimerism state after reduced-intensity conditioning transplantation (RICT), autoantibody production, and chronic GVHD (cGVHD)-related pathology. METHODS: Chimerism state, circulating anticardiolipin, and antidouble stranded DNA autoantibody (Ab) titers as well as occurrence of cGVHD-like lesions were investigated in a murine RICT model. RESULTS: We observed a novel association between mixed chimerism state, high levels of pathogenic IgG autoantibodies, and subsequent development of cGVHD-like lesions. Furthermore, we found that the persistence of host B cells, but not dendritic cell origin or subset, was a factor associated with the appearance of cGVHD-like lesions. The implication of host B cells was confirmed by a host origin of autoantibodies. CONCLUSION: Recipient B cell persistence may contribute to the frequency and/or severity of cGVHD after RICT