Cryptococcosis is an often times fatal disease caused by a yeast-like organism, Cryptococcus neoformans. Patients with cryptococcosis frequently have high levels of cryptococcal antigen in their body fluids, and antigen levels directly correlate with the severity of disease. Using a murine model we have documented that animals with large numbers of cryptococci in their tissues have high cryptococcal antigen levels in their sera and minimal delayed-type hypersensitivity (DTH) responses to cryptococcal antigen. Furthermore, if cryptococcal antigen is injected into mice at concentrations similar to those found in human systemic cryptococcosis, a complex series of suppressor cells and factors is induced which specifically suppresses the DTH response and the T cells responsible for in vitro growth inhibition of cryptococci. Two sources of cryptococcal antigen have been shown to induce suppression. One is an in vitro prepared cryptococcal culture filtrate antigen (CneF), and the other is serum from C. neoformans infected mice having a high cryptococcal antigen titer. We feel there is now a sufficient understanding of the mechanisms which down-regulate the cryptococcal cell-mediated immune response, i.e. DTH, to achieve the following proposed specific aims. The first goal of these proposed studies is to determine the effects on clearance of C. neoformans from organs after mice have been suppressed by injecting tolerizing doses of CneF or cryptococcal specific first- (Tsl) or second-order (Ts2) suppressor cells. Furthermore, clearance of Listeria monocytogenes in mice treated with suppressive doses of CneF will be monitored to assess whether or not nonspecific effects on clearance are induced by CneF. The second objective in these studies is to establish which component(s) of the cryptococcal antigen is responsible for induction of suppression. This will be achieved by fractionating the antigen by conventional methods, and testing the antigen fractions for suppressive capabilities. And, third, we will assess changes occurring at the cellular level in lymph nodes and spleens during the induction of Tsl cells in contrast to changes occurring during the induction of DTH. Parameters to be monitored will be levels of Ia antigens on lymphoid cells, IL-1 and IL-2 production, and IL-2 receptors on cells. A greater understanding of the effects of suppression and the parameters involved in the induction of suppression will provide the rationale for future investigations on effective control of the protective immune mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI015716-07
Application #
3126367
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1980-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Oklahoma Norman
Department
Type
Schools of Arts and Sciences
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
Jackson, Lydgia A; Drevets, Douglas A; Dong, Zhao-Ming et al. (2005) Levels of L-selectin (CD62L) on human leukocytes in disseminated cryptococcosis with and without associated HIV-1 infection. J Infect Dis 191:1361-7
Blackstock, Rebecca; Murphy, Juneann W (2004) Age-related resistance of C57BL/6 mice to Cryptococcus neoformans is dependent on maturation of NKT cells. Infect Immun 72:5175-80
Bauman, Sean K; Huffnagle, Gary B; Murphy, Juneann W (2003) Effects of tumor necrosis factor alpha on dendritic cell accumulation in lymph nodes draining the immunization site and the impact on the anticryptococcal cell-mediated immune response. Infect Immun 71:68-74
Nichols, Kasie L; Bauman, Sean K; Schafer, Fredda B et al. (2002) Differences in components at delayed-type hypersensitivity reaction sites in mice immunized with either a protective or a nonprotective immunogen of Cryptococcus neoformans. Infect Immun 70:591-600
Bauman, S K; Nichols, K L; Murphy, J W (2000) Dendritic cells in the induction of protective and nonprotective anticryptococcal cell-mediated immune responses. J Immunol 165:158-67
McGaha, T; Murphy, J W (2000) CTLA-4 down-regulates the protective anticryptococcal cell-mediated immune response. Infect Immun 68:4624-30
Blackstock, R; Buchanan, K L; Cherniak, R et al. (1999) Pathogenesis of Cryptococcus neoformans is associated with quantitative differences in multiple virulence factors. Mycopathologia 147:1-11
Doyle, H A; Murphy, J W (1999) Role of the C-C chemokine, TCA3, in the protective anticryptococcal cell-mediated immune response. J Immunol 162:4824-33
Blackstock, R; Buchanan, K L; Adesina, A M et al. (1999) Differential regulation of immune responses by highly and weakly virulent Cryptococcus neoformans isolates. Infect Immun 67:3601-9
Huffnagle, G B; McNeil, L K; McDonald, R A et al. (1999) Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans. J Immunol 163:4642-6

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