Ann Thorac Surg 2001;71:755-756
© 2001 The Society of Thoracic Surgeons
a Xenotransplantation Research Laboratory, Rush-PresbyterianSt. Lukes Medical Center, Chicago, Illinois, USA
Address reprint requests to Dr DiSesa, Xenotransplantation Research Laboratory, Rush-PresbyterianSt. Lukes Medical Center, 1725 West Harrison St, Chicago, IL 60612
As Originally Published in 1994:
Our primary research interest has been to induce organ graft tolerance by altering responsiveness to a specific donor without nonspecific immune suppression or chronic use of immunosuppressive drugs. Our initial experiments, such as those described in The Annals of Thorac Surgery in 1994, were based on strategic use of donor antigens to alter immune responsiveness to experimental allografts. As reported in the article, tolerance with long-term graft survival was achieved in all animals.
Because the severe shortage of human donor organs limits the utility of allotransplantation, we attempted to extend our observations in experimental allografts to a hamster to rat model of xenotransplantation in efforts to overcome the immunologic obstacles to this approach. In all experiments, no prolongation of xenograft survival was achieved.
Because of our failures with spleen cell inoculations, our focus has changed to a mouse to rat xenotransplant model using preparative bone marrow transplantation to induce a state of xenogeneic chimerism and organ graft acceptance. In these experiments , B10.BR mice were used as donors of bone marrow and cardiac grafts, and Lewis rats were recipients. Recipient rats (n = 8) received 1,100 cGy whole body radiation and subsequently were given intravenous injections of 250 to 280 x 106 murine bone marrow cells (BMCs). After 1 month, rats were typed for donor chimerism. Stable engraftment was achieved in 70% of treated rats. All mouse hematopoietic lineages developed normally in the rat. Although we did not observe signs of graft versus host disease (GVHD) in most chimeric rats, animals receiving a higher cell dose or less irradiation did show clinical signs of GVHD.
In subsequent experiments (unpublished data), primarily vascularized heterotopic cardiac xenografts were done in chimeric rats (n = 5). All donor mouse hearts transplanted in mouse-rat donor bone marrow chimeras survived indefinitely. Naive Lewis rats (n = 5) reject B10.BR mice cardiac grafts in 2 to 3 days. An unexpected pattern of rejection was observed for third party B10 murine grafts in chimeric rats. Three out of five hearts rejected at 7, 22, and 48 days, respectively; two hearts are still beating at over 70 and 80 days, as compared with control B10 hearts grafted in naive B10.BR mice (n = 3) (marrow identical to chimeric rats), which are rejected at 28 and 38 days with one heart still beating for over 50 days. Such prolongation of third-party xenograft survival in xenochimeric rats suggests that despite the absence of clinical immune compromise, these rats may not have completely normal immune function. Nevertheless, a strategy based on this approach may one day enable clinical xenotransplantation.
Finally, we have attempted to achieve mixed xenogeneic chimerism (stable combination of mouse and rat cells in rats), a state more likely to be clinically applicable. In these experiments, rats received sublethal irradiation followed by donor bone marrow cells and a single dose of cyclophosphamide. In our most recent experiments, now in progress, rats have survived following this treatment with typing showing a combination of native and donor mouse bone marrow cells. Donor-specific heart trans-plants done in these mixed chimeric animals are still viable and beating at 4 weeks.
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