| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Characterization of effector and regulatory functions of HSPs in other hosts and microbial systems should provide insight into mechanisms of virulence and protective adaptations that control virulence. Thus, it seems likely that HSPs could assume a critical importance in numerous host-parasite relationships, including resistance of host to otherwise destructively virulent parasites. At any rate, it seems clear from a series of our experiments that expression of HSP65 on peritoneal macrophages correlates dramatically with capacity to inhibit destructivc consequences of infection with both low-virulence and high-virulence strains of T.gondii.
From these bases, the expression mechanism and the biological role of HSP65 may be as follows. As first step after infection with a low-virulence of Toxoplasma, circulating gammadelta T cells recognize either Toxoplasma-derived HSP65 or host-derived HSP65, and then they accumulate and activated. At the second step, macrophages activated by gammadelta
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T cells probably via certain cytokine pathways exhibit enhanced respiratory burst releasing noxious molecules, e.g.oxygen metabolites, a major protective mechanism against intracellular pathogens like T.gondii. As the third stcp, activated macrophages synthesize endogenous HSP65 for protection against these toxic molecules, for repairment of damaged functions of themselves or for effective antigen-presentation. Finaly, either gammadelta T cells and alphabeta T cells reactive to HSP65 or alphabeta T cells specific for Toxoplasma antigen further accumulate and are activated. Such T cells directly destroy the host macrophages or activate macrophages to kill the intracellular Toxoplasma parasites.
We showed here that gammadelta T cells rather than alphabeta T cells participate in the induction of HSP65 on macrophages of hosts which have acquired resistance against toxoplasmosis. However, it stili remains undetermined about the mechanisms of expression of HSP65 and the role of this protein in the protection against this infection. Furthermore, it is very important to elucidate whether gammadelta T cells which induce the expression of HSP65 and those which accumulate recognizing HSP65 involve in the same functional subset, and whether the former and the latter subset (s) of gammadelta T cells recognize different antigens each other or the same epitope of HSP65. Moreover, it is of interest to investigate the relationship between gammadelta T cells and alphabeta T cells in protective immunity, both of which have an ability to induce this protein. Less
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