The penultimate goal of transplantation research is induction of long-term allograft acceptance without its attendent comorbidity. The best means of achieving this goal is specific tolerance. Specific tolerance implies that the organ recipient maintains immune competence and immunologically identifies the transplanted tissue as 'self'. In the laboratory, a multitude of tolerizing protocols have achieved this goal. However, it remains unclear whether these varied experimental approaches do so by common or distinct mechanisms. How this tolerance is finally achieved and whether this immunologic endpoint resembles self-tolerance is also unknown. If certain terminal events in these varying therapies are shared, then treatment more specifically directed at the common pathways can be developed. If the mechanism by which an immune system comes to distinguish self from non- self is known, than an analogue can be sought in the transplanted host. This project seeks to answer whether two tolerogenic therapies acting on fundamentally different initial signal pathways will lead to a tolerance with the same in vivo characteristics in a mouse islet allograft model. Specifically, this proposal posits that therapy directed at lymphocyte function associated antigen (anti-LFA-1, anti-adhesion) is tolerance with common features. These features are that tolerance is regulatory and 'infectious.' Further, this subpopulation of T cells which are CD4+CD25+. Understanding the root mechanisms of specific tolerance and its relationship to self-tolerance will ultimately enable appropriate targeting of the alloimmune response. With self-tolerance, the following two major hypotheses are put forward: (1) Anti-adhesion and anti-costimulatory therapy both induce regulatory tolerance which is 'infectious', and (2) transplantation tolerance, like self-tolerance, can be mapped to an essential cohort of T cells which are CD4+ and CD25+.
| Murakawa, Tomohiro; Kerklo, Michelle M; Zamora, Martin R et al. (2005) Simultaneous LFA-1 and CD40 ligand antagonism prevents airway remodeling in orthotopic airway transplantation: implications for the role of respiratory epithelium as a modulator of fibrosis. J Immunol 174:3869-79 |
| Nicolls, Mark R (2004) The clinical and biological relationship between Type II diabetes mellitus and Alzheimer's disease. Curr Alzheimer Res 1:47-54 |
| Nicolls, Mark R; Coulombe, Marilyne; Diamond, Andrew S et al. (2002) Interferon-gamma is not a universal requirement for islet allograft survival. Transplantation 74:472-7 |
| Nicolls, Mark R; Coulombe, Marilyne; Beilke, Joshua et al. (2002) CD4-dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways. J Immunol 169:4831-9 |
