Studies are proposed to obtain further information about sequences of expressed HLA class II DR and DQ genes that are responsible for the expression of determinant recognized by T lymphocytes in allo- or restricted recognition. Homozygous typing cells (HTCs), from consanguineous matings wherever possible, will be studied. DR4+ and DR2+ HTCs will be the primary focus of the proposed experiments for several reasons, including the fact that several """"""""Dw subtypes"""""""" of each of these serologically defined specificities have been defined. Individuals who are DR4+ can be divided into a number of groups based on the Dw specificities that they express as defined with HTCs, i.e. specificities recognized by T lymphocytes; these """"""""subtype"""""""" specificities include Dw4, Dw10, Dw13, Dw14, and Dw15. Likewise, DR2+ individuals can be divided into those expressing Dw2, Dw12, and LD-MN2. We consider it a special strength of this application that the same HTCs proposed herein for study by DNA techniques have been, and are continuing to be, studied in our laboratories including studies of the DR and DQ proteins, functional characterization of responding T lymphocytes, and definition of determinants recognized in allo- and restricted recognition. This should allow correlations of structure as determined by protocols in the present application with function and thus allow a better understanding of the molecular basis of cellular interactions. A number of techniques, including in vivo recombination, intra-exonic shuffling and site directed mutagenesis, are proposed to pinpoint precisely which sequences are involved in expression of determinants recognized by T lymphocytes. Normal and mutagenized genes will be studied by transfection. In addition, peptides which include sequences of interest will be evaluated in an antigen presenting cell system. Attempts will be made to generate monoclonal antibodies/antisera to determinants of interest. We believe these studies will contribute to diagnosis by providing the background information needed to study this same gene family in """"""""disease haplotypes"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022682-05
Application #
3134132
Study Section
Experimental Immunology Study Section (EI)
Project Start
1985-08-01
Project End
1990-11-30
Budget Start
1989-08-01
Budget End
1990-11-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Bach, F H; Platt, J L (1990) Transplantation: moving toward the 21st century. Contrib Nephrol 86:180-90;discussion 190-2
Reinsmoen, N L; Kaufman, D; Matas, A et al. (1990) A new in vitro approach to determine acquired tolerance in long-term kidney allograft recipients. Transplantation 50:783-90
Bach, F H (1990) Reconsideration of the mechanism of first-set vascularized allograft rejection: some concluding remarks. Hum Immunol 28:263-9
Reinsmoen, N L; Bach, F H (1990) Structural model for T-cell recognition of HLA class II-associated alloepitopes. Hum Immunol 27:51-72
Alter, B J; Bach, F H (1990) Cellular basis of the proliferative response of human T cells to mouse xenoantigens. J Exp Med 171:333-8
Noreen, H J; Davidson, M L; McCullough, J et al. (1989) HLA class II typing by restriction fragment length polymorphism (RFLP) in unrelated bone marrow transplant patients. Transplant Proc 21:2968-70
Freeman, S M; Noreen, H J; Bach, F H (1988) Oligonucleotide probing. Applications to HLA typing. Arch Pathol Lab Med 112:22-7
Fujiwara, T; Aspinall, G O; Hunter, S W et al. (1987) Chemical synthesis of the trisaccharide unit of the species-specific phenolic glycolipid from Mycobacterium leprae. Carbohydr Res 163:41-52
Freeman, S M; Noreen, H J; Dahl, C A et al. (1987) Determination of DR beta 1 alleles of DR4/Dw subtypes by oligonucleotide probing. Hum Immunol 20:1-11
Gromo, G; Ochoa, A C; Bach, F H (1987) Cytotoxic T lymphocytes: blocked differentiation at the 'poised' stage. Scand J Immunol 25:383-91

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