A recurring and somewhat frustrating theme in transplantation (Tx) biology has been that analysis of immunologic responses within the periphery has been far of less relevance than what goes on within the graft itself, at least as far as understanding many aspects of the immunobiology of allograft rejection is concerned. This point is particularly important in the area of chronic rejection, since peripheral changes appear to be few, whereas intragraft events involving tubular structures such as the vasculature are (a) ill-understood, yet (b) are diagnostic, and (c) appear paramount as determinants of deterioration in function of the transplanted organ. Analysis of events within the graft itself may be analyzed at the protein level by immunohistology and, to a far lesser extent, enzyme histochemistry, whereas studies by PCR offer only very broad insights as to mRNA expression within a tissue, and in situ hybridization remains, at best an area of promise and requiring, for practical sake, dramatic technical improvements to warrant the tremendous effort currently required to make things """"""""work"""""""". Luckily, over 15 years down the line from the early days of hybridoma technology, large panels of monoclonal antibodies (mAbs), as well as monospecific polyclonal antibodies, are available, including Abs against functionally relevant and defined proteins of prime importance to alloresponses or tolerance induction. Indeed, in some ways, this is the golden age of transplant immunohistology, since whole areas for investigation are appearing every few months and the techniques are available to ask, and answer, interesting questions of relevance to the clinician as well as the basic investigator. Unfortunately, to date, studies of the intragraft events associated with development of chronic rejection have been few and far between compared to the attention given towards acute rejection. This reflects the usual emphasis of such studies on the detection of immunoglobulins (Ig), complement and fibrin, and more recently, the types of cells present. The results have not been as insightful as expected, in part because the presence and extent of humoral reactants varied tremendously, and in part because macrophages dominate numerically in most vascularized models of allograft model rejection, whether acute or chronic, and rodent or human (3, 5, 6, 24). This Core will provide immunopathology support for the 3 projects of the program, concentrating on immunohistologic applications. We suggest that the results of such studies will be a prime means to assess the mechanisms of chronic rejection, and the effects of agents or strategies used in attempts to circumvent this process. We will focus on the answers to such questions as what leukocytes are present, what are their cytokine products, how do parenchymal cells react, and to what extent are functionally relevant molecules associated with the expression of cytokines or other inducing stimuli? The response to these questions will guide each of the projects and stimulate further experimentation.

Project Start
2000-08-01
Project End
2002-07-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
2000
Total Cost
$184,511
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Hancock, Wayne W; Gao, Wei; Shemmeri, Nida et al. (2002) Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms. Transplantation 73:1392-7
Yuan, Xueli; Dong, Victor M; Coito, Ana J et al. (2002) A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection. Transplantation 73:1736-42
Ye, Qunrui; Fraser, Christopher C; Gao, Wei et al. (2002) Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival. J Exp Med 195:795-800
Gasser, Martin; Waaga, Ana Maria; Kist-Van Holthe, Joana E et al. (2002) Normalization of brain death-induced injury to rat renal allografts by recombinant soluble P-selectin glycoprotein ligand. J Am Soc Nephrol 13:1937-45
Laskowski, Igor A; Pratschke, Johann; Wilhelm, Markus J et al. (2002) Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats. J Am Soc Nephrol 13:519-27

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