|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1998 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 1997 : ¥2,100,000 (Direct Cost : ¥2,100,000)
We have already demonstrated that both lymphotoxin and TNF receptor-I(TNFR-I) play essential roles in the formation of germinal centers (GC) and follicular dendritic cell (FDC) network in the spleen. In the present study, we have investigated the role, of lymphotoxin and TNFR-I in the establishment of spleen FDC and GC structure using reciprocal bone marrow transfer. When lymphotoxin-deficient mice were reconstituted with complement receptor 1 and 2(CR1/2)-deficient bone marrow cells, organized FDC network was identified with anti-CR1/2 monoclonal antibodies, indicating that FDC were derived from lymphotoxin-deficient recipient. Thus, expression of lymphotoxin in the bone marrow-derived cells, but not in the non-bone marrow-derived cells, is required for the maturation of FDC from non-bone marrow precursor cells. Using bone marrow transfer, we were also able to show that formation of FDC network and GC in the spleen are controlled by both lymphotoxin-expressing bone marrow-derived cells and by TNFR-I-expressing non-bone marrow-derived cells.
Because lymphotoxin is mainly produced by Th1 type helper T cells, we have also tested in vivo role of lymphotoxin in the induction of contact hypersensitivity, a prototype of delayed-type hypersensitivity reaction, with lymphotoxin-deficient mice. We have found that lymphotoxin-deficient mice exhibit dramatic impaired footpad swelling after antigenic challenge with phenyltrimethylaminoaniline (TMA). Using reciprocal bone marrow transfer, we have demonstrated that impaired contact hypersensitivity in lymphotoxin-deficient mice is due to the impaired function of bone marrow-derived cells in the skin which is essential for the sensitization phase of contact hypersensitivity reaction.
These studies clearly demonstrate that lymphotoxin plays an essential role not only in the lymphoid organogenesis but also in the contact hypersensitivity.