Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Oct 25;91(22):10700–10702. doi: 10.1073/pnas.91.22.10700

Interleukin 12 induction of interferon gamma-dependent protection against malaria.

M Sedegah 1, F Finkelman 1, S L Hoffman 1
PMCID: PMC45089  PMID: 7938013

Abstract

Intraperitoneal injection of recombinant Interleukin 12 (rIL-12) at 30 ng/day for 5 days beginning 1 to 2 days before sporozoite challenge or administration of a single dose of 150 ng of rIL-122 days before challenge protected 100% of BALB/c mice against challenge with 10(2) Plasmodium yoelii sporozoites. rIL-12-induced protection was eliminated in all mice by administration of a monoclonal antibody against interferon gamma and in 50% of mice by administration of NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase. rIL-12 protected BALB/c mice treated with cytotoxic anti-CD4 and anti-CD8 monoclonal antibodies, as well as T-cell- and B-cell-deficient severe combined immunodeficiency mice. These data suggest that rIL-12 stimulates non-B, non-T cells to produce interferon gamma that kills intrahepatic parasites by stimulating nitric oxide production. If rIL-12 proves to be well tolerated by humans, our findings support consideration of rIL-12 as an immunoprophylactic against malaria.

Full text

PDF
10700

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Chan S. H., Kobayashi M., Santoli D., Perussia B., Trinchieri G. Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J Immunol. 1992 Jan 1;148(1):92–98. [PubMed] [Google Scholar]
  2. Chan S. H., Perussia B., Gupta J. W., Kobayashi M., Pospísil M., Young H. A., Wolf S. F., Young D., Clark S. C., Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. doi: 10.1084/jem.173.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ferreira A., Schofield L., Enea V., Schellekens H., van der Meide P., Collins W. E., Nussenzweig R. S., Nussenzweig V. Inhibition of development of exoerythrocytic forms of malaria parasites by gamma-interferon. Science. 1986 May 16;232(4752):881–884. doi: 10.1126/science.3085218. [DOI] [PubMed] [Google Scholar]
  5. Finkelman F. D., Katona I. M., Mosmann T. R., Coffman R. L. IFN-gamma regulates the isotypes of Ig secreted during in vivo humoral immune responses. J Immunol. 1988 Feb 15;140(4):1022–1027. [PubMed] [Google Scholar]
  6. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hoffman S. L. Diagnosis, treatment, and prevention of malaria. Med Clin North Am. 1992 Nov;76(6):1327–1355. doi: 10.1016/s0025-7125(16)30290-5. [DOI] [PubMed] [Google Scholar]
  9. Hoffman S. L., Isenbarger D., Long G. W., Sedegah M., Szarfman A., Waters L., Hollingdale M. R., van der Meide P. H., Finbloom D. S., Ballou W. R. Sporozoite vaccine induces genetically restricted T cell elimination of malaria from hepatocytes. Science. 1989 Jun 2;244(4908):1078–1081. doi: 10.1126/science.2524877. [DOI] [PubMed] [Google Scholar]
  10. Khusmith S., Charoenvit Y., Kumar S., Sedegah M., Beaudoin R. L., Hoffman S. L. Protection against malaria by vaccination with sporozoite surface protein 2 plus CS protein. Science. 1991 May 3;252(5006):715–718. doi: 10.1126/science.1827210. [DOI] [PubMed] [Google Scholar]
  11. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Maheshwari R. K., Czarniecki C. W., Dutta G. P., Puri S. K., Dhawan B. N., Friedman R. M. Recombinant human gamma interferon inhibits simian malaria. Infect Immun. 1986 Sep;53(3):628–630. doi: 10.1128/iai.53.3.628-630.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mellouk S., Green S. J., Nacy C. A., Hoffman S. L. IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism. J Immunol. 1991 Jun 1;146(11):3971–3976. [PubMed] [Google Scholar]
  14. Mellouk S., Hoffman S. L., Liu Z. Z., de la Vega P., Billiar T. R., Nussler A. K. Nitric oxide-mediated antiplasmodial activity in human and murine hepatocytes induced by gamma interferon and the parasite itself: enhancement by exogenous tetrahydrobiopterin. Infect Immun. 1994 Sep;62(9):4043–4046. doi: 10.1128/iai.62.9.4043-4046.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mellouk S., Maheshwari R. K., Rhodes-Feuillette A., Beaudoin R. L., Berbiguier N., Matile H., Miltgen F., Landau I., Pied S., Chigot J. P. Inhibitory activity of interferons and interleukin 1 on the development of Plasmodium falciparum in human hepatocyte cultures. J Immunol. 1987 Dec 15;139(12):4192–4195. [PubMed] [Google Scholar]
  16. Schoenhaut D. S., Chua A. O., Wolitzky A. G., Quinn P. M., Dwyer C. M., McComas W., Familletti P. C., Gately M. K., Gubler U. Cloning and expression of murine IL-12. J Immunol. 1992 Jun 1;148(11):3433–3440. [PubMed] [Google Scholar]
  17. Weiss W. R., Sedegah M., Beaudoin R. L., Miller L. H., Good M. F. CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc Natl Acad Sci U S A. 1988 Jan;85(2):573–576. doi: 10.1073/pnas.85.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES