Anita S. Chong, Ph.D.

Transplantation Tolerance, Mechanisms of Rejection, and the Regulation of T and B Cell Responses to Allografts

Research Summary

The central theme of my research is to understand how the immune system discriminates between self-and non-self and how immune events subsequent to this discrimination event are regulated. The primary focus of my research on basic and translational issues of transplant tolerance. The possibility that tolerance to a transplanted organ can be induced is tremendously attractive, as it would obviate the need for expensive and dangerous chronic immunosuppression. However, it has become clear that, despite the numerous successes in inducing tolerance in rodent transplant models, transplant tolerance in humans remains an elusive goal. My laboratory has developed a tolerance-induction strategy in mice, involving the transplantation of intact bone fragments as a stable source of donor cells along with transient therapy with anti-CD40 monoclonal antibodies. We are actively investigating the mechanism for allograft tolerance, focusing on peripheral regulatory events.

A second area of investigation for my laboratory stems from the realization that the supply of human organs cannot adequately satisfy the needs of humans requiring transplantation. Thus, for transplantation to realize its potential in the treatment of human disease, alternative sources of organs must be developed. I thus decided to devote some of my research efforts to understanding the immunology of antibody-mediated xenograft rejection and accommodation.
We believe that these studies, which will elucidate what properties of antibodies determine whether they are pathogenic, non-pathogenic or even protective, will have application to xenotransplantation and also provide insights into the roles of antibodies in allotransplantation.

The third area of investigation in my laboratory focuses on issues related to the application of islet transplantation as a cure for Type I diabetes. We have developed a project that aims at defining and preventing the early inflammatory events that result early islet destruction following intraportal injection. More recently, we have embarked on studies investigation alternative sources of islet stem cells.

Selected Papers

Tanemura M, Yin D, Chong A and Galili U. (2000). Differential immune response to carbohydrate epitopes on allo- and xenografts: implications for accommodation. J. Clin. Invest. 105:301-10.

Knight DA, Hejmanowski AQ, Dierksheide JE, Williams JW, Chong AS, and Waldman WJ. (2001). Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide. Transplantation 71: 170-174.

Yin D-P, Sankary HN, Ma L-L, Shen J, Qin Y, Blinder L, Williams JW, and Chong AS-F. (2001). Lewis rat pancreas, but not cardiac xenografts, are resistant to anti- gal antibody mediated hyperacute rejection. Transplantation 71: 1385-1389.

Xu H, Shama A, Chen L, Harrison C, Wei Y, Chong AS-F, Logan JS, and Byrne GW. (2001). The structure of anti-Gal immunoglobulin genes in naïve and stimulated Gal knockout mice. Transplantation 72: 1817-1825.

Williams JW, Mital D, Chong A, Kottayil A, Millis M, Longstreth J, Huang W, Brady L, Jensik S. (2002). Experiences with leflunomide in solid organ transplantation. Transplantation 73: 358-366

Yin D-P, Ma L-L, Shen J, Byrne GW, Logan JS and Chong AS-F. (2002). CTLA-4Ig in combination with anti-CD40L prolongs xenograft survival and inhibits anti-Gal Ab production in GT-Ko mice. Am J. Transpl. 2:41-47

Xu H, Shama A, Lei Y, Okabe J, Wan H, Chong AS-F, Logan JS and Byrne GW. (2002). Development and characterization of anti-Gal B cell receptor transgenic Gal-/- mice Transplantation 73: 1549-1557.

Yin D-P, Ma L-L, and Chong AS-F. (2002). Intact active bone transplant synergizes with anti-CD40 ligand therapy to induce B cell tolerance. J. Immunology 168:5352-5358

Dujovny N, Varghese A, Shen J, Yin D, Ji S, Ma L, Finnegan A and Chong AS. (2002). Acute xenograft rejection is mediated by antibodies produced independently of TH1/TH2 cytokine profiles. Am J. Transpl. 2:520-525

Yin D-P, Ma L-L, Shen J, Zeng H and Chong AS-F. (2002). Allograft tolerance induced by intact active bone and anti-CD40L mAb therapy. Transplantation 74: 345-354

Yin D-P, Ma L-L, Sankary HN, Shen J, Zeng H, Varghese A and Chong AS-F. (2002). Role of CD4 and CD8 T cells in the rejection of concordant pancreas xenografts. Transplantation 74:1236-1241

Tanemura M, Chong A, DiSesa VJ and Galili U. (2002). Direct killing of xenograft cells by CD8+ T cells of discordant xenograft recipients. Transplantation 74; 1587-1595

Yin D-P, Dujovny N, Ma L-L, Varghese A, Shen J, Bishop K and Chong AS-F. (2003). Interferon-gamma production is specifically regulated by IL-10 in mice made tolerant with anti-CD40L and intact active bone (IAB). J Immunol 170: 853-860.

Xu H, Yin D, Naziruddin B, Chen L, Stark A, Wei Y, Lei Y, Shen J, Logan JS, Byrne GW and Chong AS-F. (2003). The in vitro and in vivo effects of anti-galactose antibodies on endothelial cell activation and xenograft rejection. J Immunol 170: 1531-1539.

Logan JS, Byrne GW, Adams C, Yin D-P, Shen J, Chong A, B Weiseman. (2003). Genetically identical cloned pigs are immunologically equivalent. Cloning Stem Cells 5: 117-21.

Ogawa H, Mohiuddin MM, Yin DP, Shen J, Chong AS, Galili U. (2004). Mouse-heart grafts expressing an incompatible carbohydrate antigen. II. Transition from accommodation to tolerance. Transplantation. 77:366-73.

Yin D-P, Zeng H, Ma L, Shen J, Byrne GW and Chong AS. (2004). Cutting Edge: Natural killer (NK) cells mediate IgG1-dependent hyperacute rejection of xenografts. J Immunol: 172(12):7235-8.

Hara M, Yin D, Dizon RF, Han M, Shen J, Chong AS and Bindokas VP. (2004). A mouse model for studying intrahepatic islet transplantation. Transplantation 78:615-618.

Li D, Gal I, Vermes C, Alegre M-L, Chong ASF, Chen L, Shao Q, Vyasheslava A, Xu X, Koreny T, Mikecz K, Finnegan A, Glant TT and Zhang J. (2004). Cutting Edge: Cbl-b: A key molecule involved in CD28- and CTLA-4 mediated T cell costimulation. J. Immunol. 173:7135-7139.

Williams JW, Yin D, Waldman J, Knight DA, Zeng H, Shen J, Ma L and Chong AS. (2004). Mechanistic Study of the malononitrileamide, FK778, in Cardiac Transplantation and CMV Infection in Rats (in press: Transplantation)

Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H and Fu Y-X. (2004). Intra-tumor depletion of CD4+ cells unmasks tumor immunogenicity leading to rejection of established tumor. (in press: J Exp Med)