David H. Sachs

Transplantation Biology Research Center
Massachusetts General Hospital
MGH-East, Building 149-9019
Boston, MA 02129
Tel: 617-726-4065
Fax: 617-726-4067
e-mail: david.sachs@tbrc.mgh.harvard.edu
5 postdoctoral fellows

This laboratory is involved in studies of transplantation biology, with an emphasis on understanding and manipulating transplantation immunity and tolerance. Current lines of investigation include:

1. Studies on the immunogeneics of the MHC, which are carried out in animal models, and involve production and characterization of monoclonal antibodies to cell surface antigens and assays of cellular and humoral immunity in the response to tissue transplants;
2. Studies on the induction of specific tolerance to both allogeneic and xenogeneic transplants by an approach which utilizes mixed bone marrow chimerism [1-3]
3. Studies on the use of retroviral vectors containing cDNA of allogeneic MHC genes to alter autologous bone marrow cells genetically and to thereby induce tolerance to the products of those genes after bone marrow reconstitution [4,5]
4. Studies in strains of miniature swine which have been developed as a large animal model for transplantation research. The availability of four different intra-MHC recombinants make this the only large animal model in which immunogenetic studies of the MHC and its role in transplantation can be performed reproducibly. We are presently studying the mechanism (cellular immunity and cytokine gene regulation) by which selective matching of MHC antigens in these animals leads to tolerance following transplantation of vascularized organs [6,7]. We are also testing strategies for crossing the xenogeneic transplantation barrier swine to primate, with the intent of utilizing our genetically defined swine as donors [8, 9, 10]. It is our hope that through understanding the mechanisms involved in transplantation immunity at the basic level we will be able to design new, clinically applicable strategies for the induction of donor specific transplantation tolerance in patients.

Papers & Publications:

1. Yamada K, Yazawa K, Shimizu A, Iwanaga T, Hisashi Y, Nuhn M, O'Malley P, Nobori S, Vagefi PA, Patience C, Fishman J, Cooper DK, Hawley RJ, Greenstein J, Schuurman HJ, Awwad M, Sykes M, Sachs DH. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2005; 11: 32-34.

2. Wong BS, Yamada K, Okumi M, Weiner J, O'malley PE, Tseng YL, Dor FJ, Cooper DK, Saidman SL, Griesemer A, Sachs DH. Allosensitization Does Not Increase the Risk of Xenoreactivity to alpha1,3-Galactosyltransferase Gene-Knockout Miniature Swine in Patients on Transplantation Waiting Lists. Transplantation. 2006;82(3):314-319.

3. Kawai T, Cosimi BA, Spitzer TR, Tolkoff-Rubn N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding R, Sharma V, FishmanJA, Dey BR, Ko DS, Hertl M, Goes NB, Williams WW, Colvin RB, Sykes M, Sachs DH. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression. N Engl J Med. 2008; 358:353-61.

4. Baron C, Sachs DH, LeGuern C. A Particular TCR beta Variable Region Used by T Cells Infiltrating Kidney Transplants. J Immunol 2001; 166(4):2589-2596.

5. Nobori S, Shimizu A, Okumi M, Samelson-Jones E, Griesemer A, Hirakata A, Sachs DH, Yamada K. Thymic rejuvenation and the induction of tolerance by adult thymic grafts. Proc Natl Acad Sci U S A. 2006; 103(50):19081-6.