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Reprogramming Immune Responses: Enabling Cellular Therapies and Regenerative Medicine

BioTransplant Incorporated, Charlestown, Massachusetts, USA

Key Words. Immune system • Reprogramming • Cellular therapy • Stem cells • Immunosuppression • Tolerance

Mary E. White-Scharf, Ph.D., 19 Johnson Road, Winchester, Massachusetts 01890, USA. Telephone: 781-729-4079; e-mail:
maryewhite{at}attbi.com

Recent advances in cellular therapies have led to the emergence of a multidisciplinary scientific approach to developing therapeutics for a wide variety of diseases and genetic disorders. Although most cell-based therapies currently consist of heterogeneous cell populations, it is anticipated that the standard of care will eventually be well-characterized stem cell lines that can be modified to meet the individual needs of the patient. Many challenges have to be overcome, however, before such "designer cells" can become a clinical reality. One of the major hurdles will be to prevent immune rejection of the therapeutic cells. A patient’s immune system may react to genetically modified or allogeneic cells as foreign, leading to their destruction. We propose that specific reprogramming of the immune system to accept cellular therapies can be accomplished by establishing hematopoietic chimerism. Successful engraftment of hematopoietic stem cells (HSCs), which have the same origin as those cells intended for therapeutic use, should lead to a re-education of the immune system so that the donor cells are recognized as self and will not be rejected. Developing safe, nontoxic protocols for reprogramming the immune system is critical to the success of this approach. Two major requirements exist for achieving stable HSC engraftment: A) depletion or displacement of host stem cells, and B) adequate immune suppression. Available data indicate that an agent such as busulfan is effective in depleting stem cells and that immune suppression can be accomplished with monoclonal antibodies that specifically target immune-reactive cells in the periphery.

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