Significance This project is attempting to develop methods of tolerance induction to facilitate use of xenotransplants in human medicine. Objectives Natural antibodies in humans and old world primates recognize a1,3 digalactose epitopes on all other animal cells. For instance, when an organ from a pig is xenotransplanted into a human or old world monkey, these antibodies in the host bind to the graft and cause Hyper-Acute Rejection (HAR), rendering the graft non-functional within minutes. We have developed a toleragen therapeutic which binds to and likely will reduce the circulating anti-a1,3 digalactose antibodies. In addition, the therapeutic has the ability to tolerize the B cells thus inhibiting the synthesis the pathogenic antibody. We propose to treat 3 rhesus monkeys (3-5 kg) via daily IV injection with 2 mg/kg of toleragen LJP 711, one monkey at the same dose and schedule with the control toleragen consisting of an irrelevant sugar epitope and one monkey with saline. If, within 60 days of treatment, circulating levels of IgG and IgM specific for the a1,3 digalactose epitope are sufficiently lowered, porcine kidney, will be xenotransplanted into experimental and control monkeys. After incidence of HAR has been quantified, the monkeys will be euthanized. Samples of spleen, lymph nodes, thymus and bone marrow will be taken at that time for in vitro analysis. Results We hope to demonstrate that a soluble toleragen can act both as a vehicle to reduce circulating antibody and to tolerize specific B cells and thus inhibit antibody mediated HAR which limits the usefulness of xenotransplantation as a human therapeutic modality. Future Directions If this line of investigation is successful we intend to examine longer time points in graft acceptance and further tolerization of the immune response.
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