This project proposes to apply current progress in a long-term study of the genetic definition of Major Histocompatibility Complex (MHC) and non-MHC products in the selectively bred canine population maintained in Cooperstown, New York, to the production of specific allogeneic unresponsiveness across minor and major donor-recipient compatibility barriers. The goal of the program is to develop an approach applicable to organ transplantation in mongrel dogs, as an eventual model for human transplantation. Recent studies have shown that the model of induction of unresponsiveness to DLA-identical canine kidney allografts provided by supralethal total body irradiation (SLTBI) and autologous bone marrow replacement (ABMTx) can be potentiated by a course of extracorporeal irradiation of the host's blood, or by in vitro pulsing od the marrow with methylprednisolone prior to ABMTx. Such potentiation was associated in both instances with elimination from the marrow of a minute (less than 5%) population of relatively large, non-lymphocytic, monocytoid cells which share morphological characteristics with cells of the dendritic series. Pilot studies in progress at this time indicate that a significant portion of such marrow cells is Ia+ and can be isolated and purified on the basis of selective adherence properties to Helix Pomatia. This project proposes to isolate and characterize such cells, and to investigate their relationship to the category of bone marrow-derived monocytoid dendritic cells of adult mammalian tissues recently shown to play a crucial role in allograft sensitization. The proposed studies will assess the potential effectiveness of depletion of such cells from the marrow, and of the use of heterologous and monoclonal antibodies directed against such cells, in potentiating the induction of unresponsiveness to renal allografts by SLTBI and ABMTx across non-MHC and MHC barriers of donor-recipient compatibility. The possible usefulness of such antisera (and monoclonal antibodies in particular) in decreasing host reactivity to renal allografts after in vivo and/or in vitro donor organ pretreatment (putatively depleting the organ of passenger dendritic cells of donor origin) will also be investigated.
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