Variation of Cytokine Patterns Related to Therapeutic Response in Diffuse Cutaneous Leishmaniasis GLO ´ RIA BOMFIM,CRISTIANE NASCIMENTO,* JACKSON COSTA,† EDGAR M. CARVALHO, MANOEL BARRAL-NETTO,* AND ALDINA BARRAL 1 Servic ¸o de Imunologia (HUPES-FAMED), Universidade Federal da Bahia, 41170-290 Salvador, Bahia, Brazil; *Centro de Pesquisas Gonc ¸alo Moniz, FIOCRUZ, 40.295-001 Salvador, Bahia, Brazil; and †Departamento de Doenc ¸a Infecciosas e Parasita ´rias, Faculdade de Medicina, Universidade Federal do Maranha ˜o, 65020 Sa ˜o Luis, Maranha ˜o, Brazil BOMFIM, G., NASCIMENTO, C., COSTA, J., CARVALHO, E. M., BARRAL-NETTO, M., AND BARRAL, A. 1996. Variation of cytokine patterns related to therapeutic response in diffuse cutaneous leishmani- asis. Experimental Parasitology 84, 188–194. Diffuse cutaneous leishmaniasis is a rare entity char- acterized by disseminated cutaneous nodules associated with specific anergy to leishmanial antigens. A low but not absent IFN- expression by cells present in cutaneous lesions has been documented during the active phase of diffuse cutaneous leishmaniasis. In this study we confirm this observation, and extend it by showing a similar pattern in peripheral blood mononuclear cells and the variation of mRNA cytokine expression pattern during different stages of the disease. During active disease, patients did not express mRNA for IFN-, while expressing mRNA for IL-2, IL-4, and IL-10. In contrast, an expression of IFN- and low IL-10 was observed after treatment-induced transient healing of cutaneous lesions. In three patients we have been able to analyze a third PBMC sample obtained after clinical relapse, documenting in all of them decreased IFN- expression with no expression of IL-10. Although there was an association between the appearance of IFN- expression and clinical improvement, with marked expression of IFN- mRNA and decreased expression of mRNA for IL-10 after treatment, this was not sufficient to prevent relapse in these patients. There- fore, it is possible that factors other than the cytokines characteristic of the Th1 and Th2 balance are implicated in the inability of diffuse cutaneous leishmaniasis patients to mount an anti-Leishmania immune response causing clinical improvement. © 1996 Academic Press, Inc. INDEX DESCRIPTIONS AND ABBREVIATIONS: leishmaniasis; cytokines; therapy; cutaneous leishmani- asis; DCL, diffuse cutaneous leishmaniasis; IFN-, interferon-gamma; IL, interleukin; PBMC, pe- ripheral blood mononuclear cells; DEPC, diethylpyrocarbonate; PCR, polymerase chain reaction. INTRODUCTION Human cutaneous leishmaniasis displays a spectral distribution, ranging from responsive mucosal leishmaniasis to the anergic form of diffuse cutaneous leishmaniasis (DCL), with lo- calized cutaneous leishmaniasis (LCL) repre- senting an intermediate state. DCL is a rare manifestation, characterized by a selective lack of cell-mediated immunity against the parasite, resulting in extensive cuta- neous involvement by nonulcerated nodules or plaques containing abundant parasites (Costa et al. 1992). DCL is a challenge to anti-parasite therapy. Following several anti- Leishmania therapeutic schemes, DCL patients exhibited clinical responses characterized by significant reduction of cutaneous lesions, but virtually all of them relapsed a few months after therapy (Costa et al. 1992). Experimental studies showed that immune response against intracellular parasites seems to be mediated by two functional subpopulations of CD4 + cells, distinguished by their pattern of cytokine production (Th1 and Th2) (Yamamura et al. 1991; Romagnani 1992). In murine leish- maniasis, resistance has been associated with Th1-type reactions (production of IL-2 and IFN-) and susceptibility with Th2-type pat- terns (production of IL-4, IL-5, and IL-10) (Scott 1991; Ca ´ceres-Dittmar et al. 1993). Studies in human active DCL showed a con- 1 To whom correspondence and reprint requests should be addressed at Servic ¸o de Imunologia, 3° andar, Hospital Universita ´rio Edgard Santos, Rua Joa ˜o das Botas s/n, Canela, SSA-Ba, Brazil. CEP 40.110.160. EXPERIMENTAL PARASITOLOGY 84, 188–194 (1996) ARTICLE NO. 0104 188 0014-4894/96 $18.00 Copyright © 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.