Platelet depletion by anti-CD41 (alphaIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines.
Accumulating evidence indicates that platelets play a critical role in the pathogenesis of experimental severe malaria (ESM) elicited by infection with Plasmodium berghei. Mice injected on day 1 of P berghei infection (early) with either anti-CD41 or anti-CD61 monoclonal antibodies (mAbs) exhibited significantly (P<.001) increased survival from ESM compared with infection controls, indicating that platelets function early in the disease. In contrast, groups of mice treated on days 4, 5, and 6 (late) with anti-CD41 mAb exhibited similar mortality as controls. Because platelet depletion by anti-CD41 mAb on day 4 of infection did not protect mice, and platelet adherence occurs on day 6, platelet adherence to endothelium is not required to mediate malarial pathogenesis. Few platelet microparticles were detected in the blood during the course of malaria, but large numbers of erythrocyte vesicles, microparticles, and debris were detected. The protective effect of early anti-CD41 mAb treatment was independent of the number of platelets, platelet microparticles, erythrocyte-platelet conjugates, and erythrocyte vesicles. Mice treated early with anti-CD41 mAb exhibited markedly altered cytokine production on day 4 of P berghei infection (increased interleukin 10 [IL-10], IL-1alpha, IL-6, interferon-gamma [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]; decreased IL-2) but no decline in coagulation factors compared with rat immunoglobulin G (IgG)-treated controls, indicating that platelets regulate the levels of pathogenic cytokines.
van der Heyde
Henri C
HC
La Jolla Bioengineering Institute and Targeted Molecules Corporation, 505 Coast Blvd, Suite 405, San Diego, CA 92037, USA. hvande@ljbi.org
Gramaglia
Irene
I
Sun
Guang
G
Woods
Catherine
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D039661:Integrin beta3 / Q000276:immunology; D008288:Malaria / Q000097:blood / Q000188:drug therapy / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D010962:Plasmodium berghei; D010973:Platelet Adhesiveness; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000276:immunology / Q000502:physiology*; D013995:Time
D000911:Antibodies, Monoclonal; D016207:Cytokines; D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb