CD4O, a 50kD glycoprotein expressed on all B cells, has been shown to play an important role in B cell development and activation. Anti CD40 monoclonal antibodies (mAb) have been shown to stimulate resting B cells to proliferate and induce Ig class switch to IgB synthesis in the presence of IL-4. The ligand for CD4O has been identified to be a glycoprotein of 39kD. Mutations or deletions of this CD40 ligand have been shown to be the cause of X-linked immunodeficiency associated with either normal or excessive IgM. Both the sequences of cDNA encoding for CD40 and its ligand have been determined. The CD40 system is readily amendable for further analysis. Recently, signalling through CD40 is shown to be distinct from that through surface Ig. Protein tyrosine phosphorylation and dephosphorylation during the early phase of engaging CD40 with anti CD4O mAb define this B cell activation pathway via CD40. Its association with a unique 28 kD tyrosine phosphorylated protein has been established. In this proposal, the CD4O activation pathway will be investigated with the following specific aims: 1) to define the molecules associated with CD4O with specific emphasis to identify associated proteins with a motif characteristic of proteins interacting with src protein tyrosine kinases (PTK), 2) to define the phosphoproteins associated with the CD40 complex, some of which are postulated to be members of the src family, and dephosphorylated and rephosphorylated rapidly during the early phase of CD40 signal transduction, 3) to explore the role of phosphatases in the CD40 signalling pathway with a special emphasis on the role of CD45 in this process, 4) to identify the structure of the 28 kD protein which is tyrosine-phosphorylated within seconds after CD40 engagement by anti CD4O mAb, 5) to explore the role of the recently described B cell cytoplasmic protein tyrosine kinase, which is deficient in human X-linked agammaglobulinemia in CD4O signal transduction, and 6) to determine whether the 21kD phosphoprotein associated with the CD40 complex is indeed p21ras. Recent studies have shown that engagement of CD4O in certain B cell tumor systems inhibit tumor growth. Thus the understanding of the CD4O signalling pathway will provide new insights in B cell activation as well as therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034546-14
Application #
2088697
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-12-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
14
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Sung, S; Rose, C E; Fu, S M (2001) Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide-pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation. J Immunol 166:1261-71
Kim, Y; Sung Ss; Kuziel, W A et al. (2001) Enhanced airway Th2 response after allergen challenge in mice deficient in CC chemokine receptor-2 (CCR2). J Immunol 166:5183-92
Kamochi, M; Kamochi, F; Kim, Y B et al. (1999) P-selectin and ICAM-1 mediate endotoxin-induced neutrophil recruitment and injury to the lung and liver. Am J Physiol 277:L310-9
Sung, S J; Taketomi, E A; Smith, A M et al. (1999) Efficient presentation of house dust mite allergen Der p 2 by monocyte-derived dendritic cells and the role of beta 2 integrins. Scand J Immunol 49:96-105
Smith, A M; Yamaguchi, H; Platts-Mills, T A et al. (1998) Prevalence of IgG anti-Der p 2 antibodies in children from high and low antigen exposure groups: relationship of IgG and subclass antibody responses to exposure and allergic symptoms. Clin Immunol Immunopathol 86:102-9
Sung, S S; Guo, C Y; Weed, J M (1997) Monoclonal antibodies against human dendritic cell-like peripheral blood monocytes activated by granulocyte/macrophage-colony-stimulating factor plus interleukin 4. Cell Immunol 182:113-24
Armerding, D; Hren, A; Callard, R E et al. (1996) Induction of cognate and non-cognate T-cell help for B-cell IgE production in relation to CD40 ligand expression. Int Arch Allergy Immunol 111:376-84
Bykowsky, M J; Haire, R N; Ohta, Y et al. (1996) Discordant phenotype in siblings with X-linked agammaglobulinemia. Am J Hum Genet 58:477-83
Gupta, S; Feng, L; Yoshimura, T et al. (1996) Intra-alveolar macrophage-inflammatory peptide 2 induces rapid neutrophil localization in the lung. Am J Respir Cell Mol Biol 15:656-63
Kornfeld, S J; Haire, R N; Strong, S J et al. (1996) A novel mutation (Cys145-->Stop) in Bruton's tyrosine kinase is associated with newly diagnosed X-linked agammaglobulinemia in a 51-year-old male. Mol Med 2:619-23

Showing the most recent 10 out of 48 publications