Experiments on lymphocyte-mediated cellular immunity in murine histoplasmosis

Congenitally athymic nude (nu/nu) mice, when injected intraperitoneally with Histoplasma capsulatum, developed a rapidly fatal disseminated infection characterized by heavy parasitization of reticuloendothelial tissues. In contrast, their heterozygous (nu/X) littermates, which possessed a functioning thymus, developed only a low-grade infection which was apparently self-limited and rarely fatal. Transplantation of thymic tissue into nu/nu mice diminished greatly the severity of infection and reduced mortality by about 50%. These studies emphasize the importance of cell-mediated immunity in host defense against histoplasmosis and suggest that the nude mouse may be a valuable model for the study of this chronic intracellular infection.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Histoplasma capsulatum infection in nude mice

Williams¹,

Graybill²,

Drutz³

1978

“…In contrast to the killing of extracellular bacterial pathogens, resident macrophages are relatively inefficient in killing certain fungal pathogens, e.g., Candida albicans (21, 30) and Cryptococcus neoformans (11,14,23). Howev-er, activated macrophages are more effective in killing these pathogens (14, 30) and can kill facultative intracellular fungal pathogens, e.g., Histoplasma capsulatum (17,18) or Coccidioides immitis (4,5).…”

mentioning

confidence: 99%

Activation of peritoneal macrophages by concanavalin A or Mycobacterium bovis BCG for fungicidal activity against Blastomyces dermatitidis and effect of specific antibody and complement

Brummer¹,

Sugar²,

Stevens³

1983

With a new short-term assay, where the reduction of CFUs in the inoculum could be measured, we investigated the killing of the dimorphic fungal pathogen Blastomyces dermatitidis in its yeast phase by murine peritoneal macrophages. Peritoneal macrophages from concanavalin A-or Mycobacterium bovis BCGtreated mice, but not resident or thioglycolate-elicited macrophages, significantly reduced the CFUs of B. dermatitidis in the inoculum. The activation of peritoneal macrophages for fungicidal activity by concanavalin A treatment was shown to be dose dependent and transient, i.e., absent after 72 h. These results indicate that it is possible for murine peritoneal macrophages to kill B. dermatitidis in vitro. The addition of specific antibody or complement or both did not enhance the killing of B. dermatitidis by these nonspecifically activated macrophages.

“…It is generally held that a critical host defense mechanism activated in response to infection by Histoplasma capsulatum is the so-called cellmediated immune response. Support for this concept is provided by several experimental studies: first, by the demonstration that lymphocytes from mice immunized by sublethal infection with H. capsulatum can mediate suppression of intracellular growth of the fungus in normal mouse macrophages (17); second, by demonstration of increased susceptibility to Histoplasma infection in congenitally athymic mice (38) or in conventional mice after treatment with antilymphocyte serum and cytotoxic agents (1,8,12); and third, by evidence for transfer of adoptive immunity against Histoplasma by spleen or peritoneal cells from immunized donors (36).…”

mentioning

confidence: 99%

Immunoregulatory Responses in Experimental Disseminated Histoplasmosis: Lymphoid Organ Histopathology and Serological Studies

Artz

Bullock

1979

To study immunoregulatory mechanisms in systemic histoplasmosis, a highly reproducible model of infection was established in C3H/Anf mice. Intravenous inoculation of 6- to 8-week-old mice with from 5 × 10 5 to 10 × 10 5 cells of yeast-phase Histoplasma capsulatum strain G-217B produced disseminated infection that resolved over an 8-week period without therapeutic intervention. Serological studies demonstrated complement-fixing antibody production to yeast- and mycelial-phase antigens of H. capsulatum . Complement-fixing antibody to the former was detected at week 1, and it peaked at week 3 and declined thereafter. Complement-fixing antibody to mycelial-phase antigen(s) appeared later (week 3) and did not peak until week 18. Grossly, the spleens of infected mice were enlarged from three to four times normal size during peak infection, whereas the thymuses were markedly involuted. Conversely, at week 8 the average spleen size was considerably smaller and the thymic mass was increased relative to the mass at week 3. Histopathologically, the paracortical regions of lymph nodes and the white pulp (periarteriolar lymphocyte sheaths) and marginal zones of the spleen were heavily infiltrated by granulomata at week 1. By week 8, the infiltrates in these areas had largely resolved. Thymocytes were severely depleted from the cortical lobules of the thymus at week 1; however, thymic cellularity was restored by week 8. These reciprocal changes in cellularity of the thymus and spleen during active infection may be of importance with reference to the disturbances of immunoregulation that we have observed in Histoplasma -infected mice.