This program project on immunoregulation in human transplantation, interdisciplinary and interinstitutional, is designed to develop and apply new knowledge of the signals involved in blocking activation of effector T cells and in promotion of an active suppressor cell response. Project 1 will explore the nature of antigens recognized by alloactivated suppressor cells in man, and will utilize novel monoclonal antibodies which subdivide the CD4(T4) and CD8(T8) subsets to isolate the suppressor circuit for more detailed study. Unusual subsets, either doubly positive for CD4+CD8+, or bearing the gamma-delta T cell receptor (T3-Ti), have been identified in blood and kidney graft infiltrates, and they will be studied as potential regulatory cells. Project 2 will expand development of monoclonal antibodies to the T200 family of molecules to use in study of the signals transduced by these molecules to preferentially activate effector or suppressor cells, and will also develop sets of anti-CD4, anti-CD8, and anti-CD3 antibodies which either block, enhance, or have no effect on T cell activation. The molecular basis of these effects will be studied in detail. Project 3 will continue to establish the optimal conditions for in vivo immunosuppression using monoclonal anti-IL- 2 receptor antibodies in a cynomolgus primate model of renal allotransplantation, and will assess other strategies for targeting activated T cells via the de novo synthesized high affinity IL-2 receptor. New antibodies of specific interest from Project 2 will be utilized in the in vitro analysis of suppressor/modulator circuits in Project 1, and some will be selected for testing as immunosuppressive agents in the primate renal transplant model. Renal transplant recipients of the Brigham and Women's and Beth Israel Hospitals will participate in a variety of immuno- therapeutic trials. Selective study of their cellular responses will be performed in Project 1. A Clinical Core consists of the investigative staff caring for the patients and responsible for protocols. A Pathology Core provides immunopathologic study of renal material from patients and monkeys for analysis of cellular subsets and states of activation. The long-term goal is to develop new approaches to regulating the T cell dependent immune response based upon more precise knowledge of regulatory circuits.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Allergy, Immunology, and Transplantation Research Committee (AITC)
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Brigham and Women's Hospital
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Duke-Cohan, J S; Morimoto, C; Rocker, J A et al. (1996) Serum high molecular weight dipeptidyl peptidase IV (CD26) is similar to a novel antigen DPPT-L released from activated T cells. J Immunol 156:1714-21
Duke-Cohan, J S; Morimoto, C; Rocker, J A et al. (1995) A novel form of dipeptidylpeptidase IV found in human serum. Isolation, characterization, and comparison with T lymphocyte membrane dipeptidylpeptidase IV (CD26). J Biol Chem 270:14107-14
Martin-Reay, D G; Kamentsky, L A; Weinberg, D S et al. (1994) Evaluation of a new slide-based laser scanning cytometer for DNA analysis of tumors. Comparison with flow cytometry and image analysis. Am J Clin Pathol 102:432-8
Dawson, A E; Cibas, E S; Bacus, J W et al. (1993) Chromatin texture measurement by Markovian analysis. Use of nuclear models to define and select texture features. Anal Quant Cytol Histol 15:227-35
Araten, D J; Lawton, T; Ferrara, J et al. (1993) In vitro alloreactivity against host antigens in an adult HLA-mismatched bone marrow transplant recipient despite in vivo host tolerance. Transplantation 55:76-82
Sayegh, M H; Khoury, S J; Hancock, W W et al. (1993) Induction of immunity and oral tolerance to alloantigen by polymorphic class II major histocompatibility complex allopeptides in the rat. Transplant Proc 25:357-8
Weinberg, D S; Weidner, N (1993) Concordance of DNA content between prostatic intraepithelial neoplasia and concomitant invasive carcinoma. Evidence that prostatic intraepithelial neoplasia is a precursor of invasive prostatic carcinoma. Arch Pathol Lab Med 117:1132-7
Duke-Cohan, J S; Morimoto, C; Schlossman, S F (1993) Targeting of an activated T-cell subset using a bispecific antibody-toxin conjugate directed against CD4 and CD26. Blood 82:2224-34
Duke-Cohan, J S; Morimoto, C; Schlossman, S F (1993) Depletion of the helper/inducer (memory) T cell subset using a bispecific antibody-toxin conjugate directed against CD4 and CD29. Transplantation 56:1188-96
Hancock, W W; Sayegh, M H; Kwok, C A et al. (1993) Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation. Transplantation 55:1112-8

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