Previous Article | Next Article 
Infection and Immunity, February 1999, p. 513-519, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Therapy with a Combination of Low Doses of
Interleukin 12 and Chloroquine Completely Cures Blood-Stage Malaria,
Prevents Severe Anemia, and Induces Immunity to
Reinfection
Karkada
Mohan,
Hakeem
Sam, and
Mary M.
Stevenson*
Centre for the Study of Host Resistance,
McGill University, and The Montreal General Hospital Research
Institute, Montreal, Quebec H3G 1A4, Canada
Received 13 August 1998/Returned for modification 14 October
1998/Accepted 11 November 1998
The immunoregulatory cytokine interleukin 12 (IL-12) induces host
resistance against experimental malaria. In this study, we tested the
feasibility of using IL-12 in combination with chloroquine (CQ) to
rescue susceptible A/J mice from lethal blood-stage Plasmodium chabaudi AS infection. Combined treatment with low doses of CQ and IL-12 resulted in a >15-fold reduction in the parasite load and
100% survival of A/J mice with established infections. Compared to
control mice, which succumbed to severe anemia, CQ-plus-IL-12-treated mice had significantly higher early- and late-stage erythroid-cell progenitors in the bone marrow and spleen, resulting in significantly higher hematocrits, erythrocyte counts, and percentages of
reticulocytes. Production of parasite-specific gamma interferon
(IFN-
) by splenocytes from these mice was upregulated >20-fold
relative to controls in parallel with enhanced IFN-
mRNA expression.
Further, enhanced responsiveness to IL-12 and increased downstream
IFN-
production in CQ-plus-IL-12-treated mice was evident from
increased mRNA expression for the
1 and
2 subunits of IL-12
receptor in the splenocytes. Moreover, this combined therapy induced
higher levels of anti-malaria antibodies than did CQ alone as well as
sterile immunity against reinfection. Because IL-12 can be used at low doses and is effective even in established infections, it may be
feasible to use this immunochemotherapeutic approach in human malaria.
*
Corresponding author. Mailing address: Montreal General
Hospital Research Institute 1650 Cedar Ave., Montreal, Quebec H3G 1A4,
Canada. Phone: (514) 937-6011 ext. 4507. Fax: (514) 934-8332. E-mail:
mcev{at}musica.mcgill.ca.
Infection and Immunity, February 1999, p. 513-519, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Metenou, S., Dembele, B., Konate, S., Dolo, H., Coulibaly, S. Y., Coulibaly, Y. I., Diallo, A. A., Soumaoro, L., Coulibaly, M. E., Sanogo, D., Doumbia, S. S., Wagner, M., Traore, S. F., Klion, A., Mahanty, S., Nutman, T. B.
(2009). Patent Filarial Infection Modulates Malaria-Specific Type 1 Cytokine Responses in an IL-10-Dependent Manner in a Filaria/Malaria-Coinfected Population. J. Immunol.
183: 916-924
[Abstract]
[Full Text]
-
DJIMDE, A. A., DOUMBO, O. K., TRAORE, O., GUINDO, A. B., KAYENTAO, K., DIOURTE, Y., NIARE-DOUMBO, S., COULIBALY, D., KONE, A. K., CISSOKO, Y., TEKETE, M., FOFANA, B., DICKO, A., DIALLO, D. A., WELLEMS, T. E., KWIATKOWSKI, D., PLOWE, C. V.
(2003). CLEARANCE OF DRUG-RESISTANT PARASITES AS A MODEL FOR PROTECTIVE IMMUNITY IN PLASMODIUM FALCIPARUM MALARIA. Am J Trop Med Hyg
69: 558-563
[Abstract]
[Full Text]
-
Chaisavaneeyakorn, S., Othoro, C., Shi, Y. P., Otieno, J., Chaiyaroj, S. C., Lal, A. A., Udhayakumar, V.
(2003). Relationship between Plasma Interleukin-12 (IL-12) and IL-18 Levels and Severe Malarial Anemia in an Area of Holoendemicity in Western Kenya. CVI
10: 362-366
[Abstract]
[Full Text]
-
Angulo, I., Fresno, M.
(2002). Cytokines in the Pathogenesis of and Protection against Malaria. CVI
9: 1145-1152
[Full Text]
-
Singh, R. P., Kashiwamura, S.-i., Rao, P., Okamura, H., Mukherjee, A., Chauhan, V. S.
(2002). The Role of IL-18 in Blood-Stage Immunity Against Murine Malaria Plasmodium yoelii265 and Plasmodium bergheiANKA. J. Immunol.
168: 4674-4681
[Abstract]
[Full Text]
-
Cravo, P., Culleton, R., Hunt, P., Walliker, D., Mackinnon, M. J.
(2001). Antimalarial Drugs Clear Resistant Parasites from Partially Immune Hosts. Antimicrob. Agents Chemother.
45: 2897-2901
[Abstract]
[Full Text]
-
Greenberg, P. L., Gordeuk, V., Issaragrisil, S., Siritanaratkul, N., Fucharoen, S., Ribeiro, R. C.
(2001). Major Hematologic Diseases in the Developing World-- New Aspects of Diagnosis and Management of Thalassemia, Malarial Anemia, and Acute Leukemia. ASH Education Book
2001: 479-498
[Abstract]
[Full Text]
-
Choudhury, H. R., Sheikh, N. A., Bancroft, G. J., Katz, D. R., de Souza, J. B.
(2000). Early Nonspecific Immune Responses and Immunity to Blood-Stage Nonlethal Plasmodium yoelii Malaria. Infect. Immun.
68: 6127-6132
[Abstract]
[Full Text]
-
Luty, A. J. F., Perkins, D. J., Lell, B., Schmidt-Ott, R., Lehman, L. G., Luckner, D., Greve, B., Matousek, P., Herbich, K., Schmid, D., Weinberg, J. B., Kremsner, P. G.
(2000). Low Interleukin-12 Activity in Severe Plasmodium falciparum Malaria. Infect. Immun.
68: 3909-3915
[Abstract]
[Full Text]
-
Martiney, J. A., Sherry, B., Metz, C. N., Espinoza, M., Ferrer, A. S., Calandra, T., Broxmeyer, H. E., Bucala, R.
(2000). Macrophage Migration Inhibitory Factor Release by Macrophages after Ingestion of Plasmodium chabaudi-Infected Erythrocytes: Possible Role in the Pathogenesis of Malarial Anemia. Infect. Immun.
68: 2259-2267
[Abstract]
[Full Text]