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very rapid intrinsic phagocytosis of the organism—when unopsonized histoplasma are incubated with human mononuclear phagocytes, 80 percent to 90 percent of them are bound to the phagocyte within 5 minutes, and within 10 minutes the same proportion have been ingested.

Other evidence that histoplasma infection leads to cell-mediated immunity include (1) granuloma formation, (2) delayed hypersensitivity, (3) proliferation by peripheral blood mononuclear cells in vitro, (4) greater susceptibility by athymic mice than in their normal littermates, and (5) the ability of T-cells from immunized mice to transfer protection to unimmunized mice. Immunity to coccidioides can also be transferred with T-cells, while T-cell depletion or impairment is associated with poor prognosis. In both cases, however, as in tuberculosis, the result is not so much the killing of the organism as the inhibiting of its growth, since the organism remains dormant for many years following the initial exposure.

In both histoplasmosis and coccidioidymosis, as in tuberculosis, the Th-1 response seems to be most important in controlling infection, at least in the mouse models of these diseases. Resting phagocytes allow the organisms to grow until they are activated by a soluble signal from the T-cells. In mice, that signal seems to be IFN-gamma, but in humans (at least for histoplasma) the signals are IL-3 and the granulocyte and macrophage colony-stimulating factor (GM-CSF). Human mononuclear phagocytes on plastic are activated by neither IFN-gamma nor tumor necrosis factor alpha (TNF-alpha).

Isolating Protective Immunogens for Histoplasma. The literature on histoplasma indicated that a sublethal inoculate of either the conidia (spores) or yeast form of H. capsulatum could protect mice from subsequent challenge, and that inactivated conidia or heat-killed yeast could also provide protection. Further analysis showed that a detergent extract of the cell wall and cell membrane from this organism could confer protective immunity, and two antigens were isolated from an extract taken from the virulent strain H. capsulatum G217-B, the standard strain used in all animal models.

Researchers were able to demonstrate (1) that one of these extracts, called HIS-62, was recognized by immune sera from mice, (2) that it stimulated proliferation of sensitized lymphocytes in immunized mice, (3) that mouse T-cell clones recognized the crude extract, and finally (4) that vaccination with HIS-62 could confer protective immunity against pulmonary histoplasmosis in three different strains of mice. Upon further analysis, researchers found that the peptide sequence from HIS-62 was highly homologous to heat shock protein 60 (hsp 60) —about 70 percent identity with hsp 60 from Saccharomyces (the nearest yeast species), 50 percent identity with hsp 60 from bacteria, and 60 percent to 70 percent identity with mouse or human hsp 60, at the amino acid level. Crossreactivity with anti-GroEL serum confirmed that HIS-62 was a member of the hsp 60 family.



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