CYTOKINE PRODUCTION IN ORGANS OF GENETICALLY SELECTED MICE FOR ANTIBODY PRODUCTION INFECTED WITH Paracoccidioides brasiliensis

THESIS: J. G. G. Pinto submitted this dissertation for his Masters in Tropical Diseases at Botucatu School of Medicine, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil, 2003.

Advisor: Professor Silvio Luis de Oliveira

ABSTRACT. Genetically selected mice for high (H) and low (L) antibody production (Selection IV-A) were used as experimental models for paracoccidioidomycosis. In a previous work, we observed that male H_IV-A animals were more susceptible to infection due to adrenal gland damage. Thus, the study of cytokine secretion pattern in the compartments frequently reached by fungi, such as the lung and adrenal, is necessary for a better understanding of the immunological mechanisms involved in P. brasiliensis infection. Male H_IV-A and L_IV-A animals were IV infected with P. brasiliensis, strain 18, and sacrificed 2, 4, 6, 8, and 10 weeks after infection. In each period, the lungs and adrenal were removed for determination of infection degree through viable fungal recovery and Th1 (IFN-g, TNF-a) and Th2 (IL-4 and L-10) profile cytokines. The H_IV-A animals showed higher infection degree in the analyzed organs. Viable fungal recovery in the lungs was higher after 4 and 8 weeks; there was a lower fungal recovery in L_IV-A animal adrenal gland after the 2^nd week and total fungal elimination after the 8^th week. In relation to Th2 cytokine determination, there was an inhibition of IL-4 production in organs of infected animals when compared to control; this varied according to organ and period studied. Il-10 production in both organs was also lower than in non-infected animals. Interesting data were obtained from Th1 cytokine determination: IFN-g production increased in both organs, mainly in the L_IV-A strain suprarenal after 8 and 10 weeks when these animals showed total fungal elimination. A significant difference was seen between H_{IV-A and} L_IV-A strains in relation to TNF-a production in the organs and all time periods, the latter producing a higher level of this cytokine, mainly in the adrenal. These results indicate the high susceptibility of H_IV-A animals to P. brasiliensis infection, mainly the adrenal involvement. The higher production of TH1 profile cytokines by L_IV-A strain may be associated with these animals’ resistance to fungi, as shown in previous works. Our data show the importance of this experimental model in the study of adrenal involvement in paracoccidioidomycosis , since this gland can be highly compromised in patients, leading to the development of Addison’s disease.

KEY WORDS: experimental paracoccidioidomycosis; Biozzi mice; cytokines; IV-A selection; suprarenal.

CORRESPONDENCE TO: J. G. G. Pinto – Rua Miguel Catharino, 159, Vila Nova Botucatu, 18608-210, Botucatu, São Paulo, Brasil. Mobile: 55 14 97039260. E-mail:joaogustavog@yahoo.com.br