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Capstone

Hematopoietic Stem Cell (HSC) Chimerism in Induced Donor-Specific Allograft Immunotolerance

1 August 2007

Abstract

Purpose- To assess the state of the art in the development and practicability of the concept that full and permanent donor specific immunotolerance within a host to allogeneic transplant can be induced with pretransplant hematopoietic stem cell chimerism, i.e., a mixed host/donor immunopotent cell phylogeny in the host after an initial HSC transplant, which becomes a plural immune system mutually tolerant to both host and donor immune codes, thus sparing any immunological crossreactivity between the host and HSC donor. The HSC donor may then hypothetically donate any other tissue without the need for immunosuppressive therapy in the host.

Methods- A selective representational literature review

Results- Mixed chimerism donor specific immunotolerance is routinely applied in transplant medicine and hematology to reduce dependence on transplant immunosuppressive therapy, augment host immunocompetence with donor lymphocytes, and for a graft versus tumor selectivity against dysplasias. Long term effect and weaning off posttransplant immunosuppressive therapy has been preliminarily achieved and is under study. However, the utilization of the full hypothetical concept is immature, and still requires partially myeloablative conditioning with radio.active or chemical regimens, paradoxical immunosuppressive therapy at induction, growth factor stimulation, and clonal T-cell deletion therapy. Pure immunoprivileged hematopoietic stem cells usually do not engraft without partially myeloablative therapy and the facilitation of mature donor T-cells. Such facilitator cells are not immunoprivileged and thus require paradoxical host immunosuppression anyway in both the host versus graft sense and vice versa. The partially depleted host+donor HSC bed does not repopulate well without growth factor therapy. There is a temporal discrepancy between the thymic reconditioning, i.e., the natural clonal deletion of existing mature T -cells with respect to the differentiated or repopulated phylogeny of the mixed host/donor HSC bed. This represents a potential late rejection mechanism even if the initial HSC engraftment were possible without mature donor Tcells, requiring clonal deletion therapy with specific anti-T-cell . antibodies.

Conclusions- A cross representation of articles indicate that full use of the mixed chimerism concept specifically to avoid transplant rejection without any immunosuppression is not practicable at this time. Each of these necessities represents treatment risks and failures in themselves despite the realized and hypothetical potentials. The paradoxical necessities of partially myeloablative conditioning and immunosuppression to achieve stable mixed immunological chimerism in the host defeats the purpose of doing it unless the host's outlook is already grave. If the host must be exposed to risks equivalent to myeloablation, immunosuppression, and graft versus host disease anyway, mixed chimerism is well-practiced as augmentative donor-specific immunotolerance induction, and is emerging as a way to replace immunosuppressive therapy later on in the course of the life of a graft, but it is not yet practicable by itself. In order to become practicable, the mechanisms requiring myeloablation and of mature donor T-cell facilitation must be elucidated and compensated for, and specific clonal deletion of existing mature host T-cells must be more perfected for prophylactic use without compromising general host immunocompetence. Arguably the only component of the practicable concept with a risk low enough for elective use is growth factor therapy. This currently relegates the concept to only non-elective transplants and dysplasias wherein these risks are already incurred, but with the promising prospect that immunosuppressive therapy may not necessarily be lifelong anymore.


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