Interferon gamma increases survival in urine experimental cryptococcosis

Bava, Amadeo J.; Afeltra, Javier; Negroni, Ricardo; Diez, Roberto A.

doi:10.1590/S0036-46651995000500003

Abstracts

Systemic disease by Cryptococcus neoformans (C. neoformans) is a common opportunistic infection in immunodeficient patients. Cellular immunity seems to be the most important determinant of resistance. The aim of this study was to assess the effect of recombinant rat interferon gamma (IFN-gamma) in murine cryptococcosis (Balb/c mice infected by IP route with the Rivas strain of C. neoformans), evaluating survival time, macroscopic and microscopic examination of the organs, and massive seeding of brain homogenate. IFN-gamma treatment, at a daily dose of 10,000 IU, did not modify significantly these variables when mice were challenged with a high inoculum (10(7) yeasts) and treatment was delayed to 5 days after infection (median survival 21 days in control mice vs. 23 days in IFN-treated). Another set of experiments suggested that IFN-gamma treatment, at a dose of 10,000 IU/day, begun at the moment of infection could be useful (it prolonged survival from 20 to 28 days, although the difference did not achieve statistical signification). When used simultaneously with infection by 3.5 x 10(5) yeasts, IFN-gamma at 10,000 IU/day for 15 days significantly prolonged survival of mice (p = 0.004). These results suggest that, depending on the experimental conditions, IFN-gamma can improve survival of mice infected with a lethal dose of C. neoformans.

Cryptococcosis; Interferon gamma; Experimental treatment

Se evaluó la efectividad del interferon-gamma (IFN-gamma) recombinante de rata en un modelo experimental de criptococosis desarollado en ratones Balb/C inoculados por vía intraperitoneal con la cepa Rivas de Cryptococcus neoformans (C. neoformans). Se tuvieron en cuenta el tiempo de sobrevida de los animales, el aspecto macroscópico de los órganos en la autopsia, la presencia de levaduras capsuladas en los tejidos y la siembra masiva de un homogenato de cerebro. El tratamiento con IFN-gamma, en dosis diarias de 10.000 UI, no modificó estos parámetros cuando la dosis infectante fue de 10(7) levaduras y el tratamiento se retardó 5 días post-infección (media de sobrevida de 21 vs. 23 días en los grupos de control y tratados con IFN-gamma, respectivamente). En otros experimentos observamos una prolongación del tiempo de sobrevida (aunque no significativo) de 20 a 28 días, cuando el tratamiento con 10.000 UI/día de IFN-gamma comenzó en el momento de la infección experimental. Cuando el IFN-gamma, a razón de 10.000 UI/día durante 15 días, fue administrado simultáneamente con una dosis infectante de 3,5 x 10(5) levaduras, el tiempo de sobrevida de los animales aumentó significativamente (p=0.004). Los resultados obtenidos sugieren que, dependiendo de las condiciones experimentales, IFN-gamma prolonga el tiempo de sobrevida de ratones infectados con una dosis letal de C. neoformans.

MICOLOGY

Interferon gamma increases survival in urine experimental cryptococcosis

El Interferon gamma incrementa la sobrevida de un modelo experimental murino de criptococosis

Amadeo J. Bava; Javier Afeltra; Ricardo Negroni; Roberto A. Diez

Centro de Micologia, Facultad de Medicina (UBA), Paraguay 2155 Piso 11, 1121 Buenos Aires, Argentina, and Inmunología Clínica, IO/IIHEMA

^{Correspondence to} Correspondence to: A.J. Bava, MD c/o R. A. Diez Academia Nacional de Medicina Pacheco de Melo 3081 1425 Buenos Aires, Argentina Fax(541) 805-3415, phone (541) 805-6461, ext. 255

SUMMARY

Systemic disease by Cryptococcus neoformans (C. neoformans) is a common opportunistic infection in immunodeficient patients. Cellular immunity seems to be the most important determinant of resistance. The aim of this study was to assess the effect of recombinant rat interferon gamma (IFN-g) in murine cryptococcosis (Balb/c mice infected by IP route with the Rivas strain of C. neoformans), evaluating survival time, macroscopic and microscopic examination of the organs, and massive seeding of brain homogenate. IFN-g treatment, at a daily dose of 10,000 IU, did not modify significantly these variables when mice were challenged with a high inoculum (10⁷ yeasts) and treatment was delayed to 5 days after infection (median survival 21 days in control mice vs. 23 days in IFN-treated). Another set of experiments suggested that IFN-g treatment, at a dose of 10,000 IU/day, begun at the moment of infection could be useful (it prolonged survival from 20 to 28 days, although the difference did not achieve statistical signification). When used simultaneously with infection by 3.5 x 10⁵ yeasts, IFN-g at 10,000 IU/day for 15 days significantly prolonged survival of mice (p = 0.004). These results suggest that, depending on the experimental conditions, IFN-g can improve survival of mice infected with a lethal dose of C. neoformans.

Keywords: Cryptococcosis; Interferon gamma; Experimental treatment.

RESUMEN

Se evaluó la efectividad del interferon-g (IFN-g) recombinante de rata en un modelo experimental de criptococosis desarollado en ratones Balb/C inoculados por vía intraperitoneal con la cepa Rivas de Cryptococcus neoformans (C. neoformans).

Se tuvieron en cuenta el tiempo de sobrevida de los animales, el aspecto macroscópico de los órganos en la autopsia, la presencia de levaduras capsuladas en los tejidos y la siembra masiva de un homogenato de cerebro.

El tratamiento con IFN-g, en dosis diarias de 10.000 UI, no modificó estos parámetros cuando la dosis infectante fue de 10⁷ levaduras y el tratamiento se retardó 5 días post-infección (media de sobrevida de 21 vs. 23 días en los grupos de control y tratados con IFN-g, respectivamente).

En otros experimentos observamos una prolongación del tiempo de sobrevida (aunque no significativo) de 20 a 28 días, cuando el tratamiento con 10.000 UI/día de IFN-g comenzó en el momento de la infección experimental. Cuando el IFN-g, a razón de 10.000 UI/día durante 15 días, fue administrado simultáneamente con una dosis infectante de 3,5 x 10⁵levaduras, el tiempo de sobrevida de los animales aumentó significativamente (p=0.004).

Los resultados obtenidos sugieren que, dependiendo de las condiciones experimentales, IFN-g prolonga el tiempo de sobrevida de ratones infectados con una dosis letal de C. neoformans.

Full text available only in PDF format.

Texto completo disponible sólo en PDF.

ACKNOWLEDGMENTS

We are indebted to Dr. E.T. Falcoff for encouraging. Roussel-Uclaf (Romainville, France) kindly provided the recombinant IFN-g used in this study.

Recebido para publicação em 27/03/1995

Aceito para publicação em 13/07/1995

1. BADARO, R.; FALCOFF, E.; BADARO, F.S. et al - Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. New Engl. J. Med., 322: 16-21, 1990.
2. BALKWILL, F.R. & BURKE, F. - The cytokine network. Immunol. today, 10: 299-304, 1989.
3. BAVA, A.J. & NEGRONI, R. - Comparative study of four antifungal drugs in an experimental model of murine cryptococcosis. Mycopathologia (Den Haag), 108: 81-86, 1989.
4. BAVA, A.J. & NEGRONI, R. - Comparative study of six antifungal treatments in an experimental model of murine cryptococcosis. Europ. J. Epidem., 8: 422-426, 1992.
5. BEAMAN, L. - Fungicidal activation of murine macrophages by recombinant murine gamma naterferon. Infect. Immun., 55: 2951-2955, 1987.
6. DIAMOND, R.D. - Cryptococcus neoformans. In: MANDELL, G.L.; DOUGLAS, R.G. & BENNETT, J.E. Principles and practice of infectious disease. New York, John Wiley, 1990. p. 1980-1989.
7. FLESCH, I.E.A.; SCHWAMBERGER, G. & KAUFMANN, S.H.E. - Fungicidal activity of IFN - activated macrophages: extracellular killing of Cryptococcus neoformans. J. Immunol., 142: 3219-3224, 1989.
8. GLANTZ, S.A. - Primer of biostatistics. New York, Mac Graw Hill, 1987, p. 1-352.
9. GRANGER, D.L., PERFECT, J.R. & DURACK, D.T. - Macrophage-mediated fungistasis in vitro: requirements for intracellular and extracellular cytotoxicity. J. Immunol., 136: 672-680, 1986.
10. LANE, T.E.; WU-HSIEH, B.A. & HOWARD, D.T. - Iron limitation and the gamma interferon-mediated anti-histoplasma state of murine macrophages. Infect. Immun., 59: 2274-2278, 1991.
11. LEVITZ, S.M. - Activation of human peripheral blood mononuclear cells by interleukin-2 and granulocyte-macrophage colony-stimulating factor to inhibit Cryptococcus neoformans. Infect. Immun., 59: 3393-3397, 1991.
12. LEVITZ, S.M. & DI BENEDETTO, D.J. - Paradoxical role of capsule in murine bronchoalveolar macrophage-mediated killing of Cryptococcus neoformans. J. Immunol., 142: 659-665, 1989.
13. MODY, C.H.; LIPSCOMB, M.F., STREET, N.E. & TOEWS, G.B. - Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans. J. Immunol., 144: 1472-1477, 1990.
14. MUKHERJEE, J.; PIROFSKI, L.A.; SCHARFF, M.D. & CASADEVALL, A. - Antibody-mediated protection in mice with lethal intracerebral Cryptococcus neoformans infection. Proc. nat. Acad. Sci. (Wash), 90: 3636-3640, 1993.
15. MURRAY, H.W.; RUBIN, B.Y.; MASUR, H. & ROBERTS, R.B. - Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. New Engl. J. Med., 310: 883-888, 1984.
16. MURRAY, H.W.; SCAVUZZO, D.A.; KELLY, C.D.; RUBIN B.Y. & ROBERTS, R.B. - T4+ cell production of interferon gamma and the clinical spectrum of patients at risk for and with acquired immunodeficiency syndrome. Arch. intern. Med., 148: 1613-1616, 1988.
17. NATHAN, C.F.; KAPLAN, G.; LEWIS, W.R. & COHN, Z.A. - Local and systemic effects of intradermal recombinant interferon-g in patients with lepromatous leprosy. New Engl. J. Med., 315: 6-15, 1986.
18. NATHAN, C.F.; MURRAY, H.W.; WEIBE, M.E. & RUBIN, B.Y. - Identification of interferon gamma as the lymphokine that activates human macrophages oxidative metadolism and antimicrobial activity. J. exp. Med., 158: 670-689, 1983.
19. NEGRONI, R. & FINQUELIEVICH, J.L. - Criptococosis subaguda experimental, en ratas Wistar (In Spanish). Medicina (B.Aires), 47: 133-138, 1987.
20. ROZENBERG-ARSKA, M. & VISER, M.R. - Infectious disease therapy in the 1990s. Where are we heading? Drugs, 43: 629-636, 1992.
21. SAAG, M.S.; PODWERLY, W.G.; CLOUD, G.A. et al - Comparison of amphotericin B with fluconazole in the treatment of acute AIDS- associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. New Engl. J. Med., 326: 83-89, 1992.
22. STEVENS, D.A. - Interferon-gamma and fungal infections. In: JAFFE, H.S., BUCALO, L.R. & SHERWIN, S.A., ed. Anti-infective applications of interferon-gamma. New York, Marcel Dekker, 1991. p. 279-291.

Correspondence to:

A.J. Bava, MD c/o R. A. Diez

Academia Nacional de Medicina

Pacheco de Melo 3081

1425 Buenos Aires, Argentina

Fax(541) 805-3415, phone (541) 805-6461, ext. 255

Publication Dates

Publication in this collection
21 Sept 2006
Date of issue
Oct 1995

History

Accepted
13 July 1995
Received
27 Mar 1995

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. BADARO, R.; FALCOFF, E.; BADARO, F.S. et al - Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. New Engl. J. Med., 322: 16-21, 1990.

[2] 2. BALKWILL, F.R. & BURKE, F. - The cytokine network. Immunol. today, 10: 299-304, 1989.

[3] 3. BAVA, A.J. & NEGRONI, R. - Comparative study of four antifungal drugs in an experimental model of murine cryptococcosis. Mycopathologia (Den Haag), 108: 81-86, 1989.

[4] 4. BAVA, A.J. & NEGRONI, R. - Comparative study of six antifungal treatments in an experimental model of murine cryptococcosis. Europ. J. Epidem., 8: 422-426, 1992.

[5] 5. BEAMAN, L. - Fungicidal activation of murine macrophages by recombinant murine gamma naterferon. Infect. Immun., 55: 2951-2955, 1987.

[6] 6. DIAMOND, R.D. - Cryptococcus neoformans. In: MANDELL, G.L.; DOUGLAS, R.G. & BENNETT, J.E. Principles and practice of infectious disease. New York, John Wiley, 1990. p. 1980-1989.

[7] 7. FLESCH, I.E.A.; SCHWAMBERGER, G. & KAUFMANN, S.H.E. - Fungicidal activity of IFN - activated macrophages: extracellular killing of Cryptococcus neoformans. J. Immunol., 142: 3219-3224, 1989.

[8] 8. GLANTZ, S.A. - Primer of biostatistics. New York, Mac Graw Hill, 1987, p. 1-352.

[9] 9. GRANGER, D.L., PERFECT, J.R. & DURACK, D.T. - Macrophage-mediated fungistasis in vitro: requirements for intracellular and extracellular cytotoxicity. J. Immunol., 136: 672-680, 1986.

[10] 10. LANE, T.E.; WU-HSIEH, B.A. & HOWARD, D.T. - Iron limitation and the gamma interferon-mediated anti-histoplasma state of murine macrophages. Infect. Immun., 59: 2274-2278, 1991.

[11] 11. LEVITZ, S.M. - Activation of human peripheral blood mononuclear cells by interleukin-2 and granulocyte-macrophage colony-stimulating factor to inhibit Cryptococcus neoformans. Infect. Immun., 59: 3393-3397, 1991.

[12] 12. LEVITZ, S.M. & DI BENEDETTO, D.J. - Paradoxical role of capsule in murine bronchoalveolar macrophage-mediated killing of Cryptococcus neoformans. J. Immunol., 142: 659-665, 1989.

[13] 13. MODY, C.H.; LIPSCOMB, M.F., STREET, N.E. & TOEWS, G.B. - Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans. J. Immunol., 144: 1472-1477, 1990.

[14] 14. MUKHERJEE, J.; PIROFSKI, L.A.; SCHARFF, M.D. & CASADEVALL, A. - Antibody-mediated protection in mice with lethal intracerebral Cryptococcus neoformans infection. Proc. nat. Acad. Sci. (Wash), 90: 3636-3640, 1993.

[15] 15. MURRAY, H.W.; RUBIN, B.Y.; MASUR, H. & ROBERTS, R.B. - Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. New Engl. J. Med., 310: 883-888, 1984.

[16] 16. MURRAY, H.W.; SCAVUZZO, D.A.; KELLY, C.D.; RUBIN B.Y. & ROBERTS, R.B. - T4+ cell production of interferon gamma and the clinical spectrum of patients at risk for and with acquired immunodeficiency syndrome. Arch. intern. Med., 148: 1613-1616, 1988.

[17] 17. NATHAN, C.F.; KAPLAN, G.; LEWIS, W.R. & COHN, Z.A. - Local and systemic effects of intradermal recombinant interferon-g in patients with lepromatous leprosy. New Engl. J. Med., 315: 6-15, 1986.

[18] 18. NATHAN, C.F.; MURRAY, H.W.; WEIBE, M.E. & RUBIN, B.Y. - Identification of interferon gamma as the lymphokine that activates human macrophages oxidative metadolism and antimicrobial activity. J. exp. Med., 158: 670-689, 1983.

[19] 19. NEGRONI, R. & FINQUELIEVICH, J.L. - Criptococosis subaguda experimental, en ratas Wistar (In Spanish). Medicina (B.Aires), 47: 133-138, 1987.

[20] 20. ROZENBERG-ARSKA, M. & VISER, M.R. - Infectious disease therapy in the 1990s. Where are we heading? Drugs, 43: 629-636, 1992.

[21] 21. SAAG, M.S.; PODWERLY, W.G.; CLOUD, G.A. et al - Comparison of amphotericin B with fluconazole in the treatment of acute AIDS- associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. New Engl. J. Med., 326: 83-89, 1992.

[22] 22. STEVENS, D.A. - Interferon-gamma and fungal infections. In: JAFFE, H.S., BUCALO, L.R. & SHERWIN, S.A., ed. Anti-infective applications of interferon-gamma. New York, Marcel Dekker, 1991. p. 279-291.

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