This proposal is based on the hypothesis that there exists a relationship between the expression of certain T-cell functions and the context in which a T-cell recognizes particular MHC molecules. The following aims are included in the studies proposed herein: 1. Investigation of the functional, genetic restriction and antigen specificity profiles of TLC's directed at influenza viral hemagglutinin determinants but restricted by different interaction products encoded within HLA-D subregions such as HLA-DR, DQ and DP. 2. Elucidation of the nature and extent of class II molecules expressed by human T-cells and the role of these molecules in regulating direct communication between functional T-cells. The antigen specificity of human T-cell clones will be closely defined with synthetic peptides corresponding to the influenze hemagglutinin molecule. The genetic restriction of these clones will be grossly defined in panel studies and in family segregation analyses; restriction fine specificity will be probed using monoclonal antibodies specific for D-region class II molecules. The data will be examined for correlations between T-cell spedificity and function as an approach to understanding the genetic control of human immune responsiveness. The significance of this proposal is based on the need to develop in vitro models of human immunoregulation; it should contribute information useful to areas such as basic human genetics, transplantation biology and immune pathology. Potential conceptual applications exist with respect to allergy, anergic states (e.g., deficient responses to parasitic organisms in schistosomiasis and leprosy) and autoimmunity. In all of these areas, the determinant structures on disease-related antigens and their perhaps subtle interactions with HLA-encoded, class II restriction elements are poorly understood and need explanation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022832-04
Application #
3134393
Study Section
Immunobiology Study Section (IMB)
Project Start
1985-04-01
Project End
1989-11-30
Budget Start
1988-04-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Brady, M S; Lee, F; Petrie, H et al. (2000) CD4(+) T cells kill HLA-class-II-antigen-positive melanoma cells presenting peptide in vitro. Cancer Immunol Immunother 48:621-6
Brady, M S; Eckels, D D; Lee, F et al. (1999) Cytokine production by CD4+ T-cells responding to antigen presentation by melanoma cells. Melanoma Res 9:173-80
Brady, M S; Eckels, D D; Ree, S Y et al. (1996) MHC class II-mediated antigen presentation by melanoma cells. J Immunother Emphasis Tumor Immunol 19:387-97
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Wu, S; Gorski, J; Eckels, D D et al. (1996) T cell recognition of MHC class II-associated peptides is independent of peptide affinity for MHC and sodium dodecyl sulfate stability of the peptide/MHC complex. Effects of conservative amino acid substitutions at anchor position 1 of influenza matrix pr J Immunol 156:3815-20
Kawaguchi, M; Eckels, D D (1995) Differential activation through the TCR-CD3 complex affects the requirement for costimulation of human T cells. Hum Immunol 43:136-48
Garlie, N K; Eckels, D D (1994) Idiotype-specific autologous T-cell interactions restricted by HLA-DR. Hum Immunol 39:69-75
Geiger, M J; Bull, M; Eckels, D D et al. (1993) Amplification of complementary DNA from mRNA with unknown 5' ends by one-way polymerase chain reaction. Methods Enzymol 218:321-35
Hurley, C K; Steiner, N; Wagner, A et al. (1993) Nonrandom T cell receptor usage in the allorecognition of HLA-DR1 microvariation. J Immunol 150:1314-24

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