There is increasing evidence that graft-specific antibodies (Abs) play a dominant role in xenograft rejection, and a critical role in allograft rejection. While anti-graft IgM antibodies are probably the most critical initiators of hyperacute rejection of xenografts and allografts, the roles of anti-graft IgG antibodies in transplantation rejection have not been well characterized. In this proposal we have focussed on Abs against galactose-alpha1,3- galactose (Gal) that play a dominant role in xenograft rejection. We have generated a series of 53 anti-Gal producing hybridomas, and have extensively characterized these anti-Gal monoclonal Abs (mAbs) in vitro. We have also developed a novel model system using double knockout mice, deficient in the galactosyltransferase (GT) and recombination-activating (Rag-1) genes, as recipients of Gal-expressing heart grafts in conjunction with passively transfused anti-Gal IgG monoclonal Abs (mAbs). We will use this model to investigate the mechanisms by which anti-Gal mAbs elicit graft rejection or induce accommodation. Graft accommodation is defined as the survival of grafted organs in the presence of anti-graft Abs and normal complement levels.
The specific aims of this proposal are to define the mechanisms of anti-Gal IgGl-mediated rejection and graft accommodation. We have recently demonstrated that an anti-Gal IgG1 antibody has the ability to induce a form of very acute rejection (VAR) that is distinct from the hyperacute rejection mediated by anti-Gal IgG3. Specifically, we will investigate the contribution of complement and NK cell-mediated inflammatory processes to the pathogenicity of anti-Gal IgGl. We will also define the in vivo mechanisms of IgG-mediated graft accommodation. We observed that the administration of purified anti-Gal IgG mAbs at doses that do not elicit xenograft rejection is not a neutral event, but induces graft accommodation. Thus, xenografts pretreated with low doses of anti-Gal IgG1 acquire resistance and do not succumb to rejection when challenged with high doses of anti-Gal IgG1 mAbs. We propose to characterize the in vivo conditions that favor the development of graft accommodation and to define the molecular mechanisms of anti-Gal IgG-induced accommodation. We anticipate that these studies will lead to an improved understanding of the roles of antibodies in graft rejection and accommodation, and the development of new strategies to improve graft function in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI052464-01A1
Application #
6616946
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
2003-09-01
Project End
2007-12-31
Budget Start
2003-09-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$127,083
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Ding, Jin Wen; Zhou, Tingting; Zeng, Huasong et al. (2008) Hyperacute rejection by anti-Gal IgG1, IgG2a, and IgG2b is dependent on complement and Fc-gamma receptors. J Immunol 180:261-8
Li, Yijin; Ma, Lianli; Yin, Dengping et al. (2008) Long-term control of alloreactive B cell responses by the suppression of T cell help. J Immunol 180:6077-84
Xiang, Zhidan; Ma, Lian-Li; Manicassamy, Santhakumar et al. (2008) CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation 85:1205-11
Ding, J Wen; Zhou, T; Ma, L et al. (2008) Expression of complement regulatory proteins in accommodated xenografts induced by anti-alpha-Gal IgG1 in a rat-to-mouse model. Am J Transplant 8:32-40
Kirk, A D; Baldwin, W M; Cascalho, M I et al. (2007) American society of transplantation symposium on B cells in transplantation: harnessing humoral immunity from rodent models to clinical practice. Am J Transplant 7:1464-70

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