TOLEROGENIC STEM CELL TRANSPLANTATION FOR ARTHRITIS

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Immunoablation followed by autologous stem cell transplantation holds the promise of providing a cure for some types of severe autoimmune disease. The goal of this proposal is to examine the therapeutic potential of autologous stem cell transplantation by studying the effects of a pseudoautologous bone marrow transplant (PA-BMT) on fully-developed collagen-induced arthritis (CIA) in mice. We postulate that stem cell transplantation will provide a window of opportunity in which treatments that were formerly effective only when given before the onset of disease will now be therapeutic in mice with established disease. We will thus exploit the process of reconstitution of the immune system to reestablish the tolerance that was broken when autoimmunity was induced. The key to this process will be the use of specific treatments to render the reemerging immune system tolerant to the antigen(s) driving the autoimmune process. CIA, a well- characterized model of inflammatory polyarthritis, was chosen because it is partially responsive to immune ablation and rescue with either allogeneic or syngeneic bone marrow cells. It thus provides a model in which the proposed treatments can be judged by their ability to improve or worsen the results of transplantation alone. Preliminary experiments indicate that induction of tolerance to type II collagen in naive mice is significantly enhanced by the prior use of PA-BMT. Initial experiments will determine the optimum protocol for a PA-BMT as judged by the level of CIA activity that persists after the transplant. Subsequent experiments will evaluate the potential of post-transplant immunotherapy to eliminate the residual CIA activity that persists after transplant. The special case of antigen-specific therapy will be examined first. Protocols using collagen, which are capable of inducing tolerance if given before but not after arthritis, will be tested to determine if they regain effectiveness when used in the immediate post transplant period. The second set of experiments will explore the concept of non-CII specific immunotherapy with the aim of shifting the balance to favor tolerance rather than active response to autoantigens during rematuration of the immune system. The response of arthritis to the treatments will be correlated with studies of the level of immunologic reconstitution as well as in vivo and in vitro T and B cell responses to CII.