The presence of high levels of antibodies in humans and baboons directed to galactose alpha1-3 galactose (Gal) epitopes on pig vascular endothelium leads to antibody-mediated destruction of pig organs transplanted into these higher species. A successful method of depleting these anti-Gal antibodies is currently in use, but the return of antibody cannot be prevented. The studies detailed in this Project are aimed towards achieving a state of tolerance in baboons to the Gal epitope, and are largely based on successful studies in mice reported from our center.
In Aim %1, this goal will be sought by transducing the baboon's own bone marrow cells with the gene for alpha 1,3 galactosyltransferase. Reinfusion of the transduced cells into the """"""""conditioned"""""""" baboon (prepared by irradiation, splenectomy, and drug therapy) will result in the expression of Gal on the baboon's cells. This will result in deletion or anergy of Gal-reactive B cells and cessation of production of this antibody.
In Aim #2, this goal will be achieved by successful engraftment of pig bone marrow cells in similarly conditioned baboons. Leukapheresis of pigs treated with pig-specific cytokines (bone marrow cell growth factors) results in large numbers of leukocytes being obtained (>100 x 10^10) in which there are significant numbers of stem cells.
Aim #3 is directed towards facilitating Aims #1 and 2 by providing an immunotoxin, based on a murine monoclonal antibody directed to the CD38 receptor coupled to ricin A, has been demonstrated to inhibit plasma cell function. These studies are intricately intertwined with those of Project 2 and will provide a major source of baboon blood samples and pig tissues for Projects 3 and 4. The work performed in Project 1 will provide information that will greatly facilitate Project 2.
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