Effects of in vivo Administration of Anti-IL-10 or Anti-IFN-.GAMMA. Monoclonal Antibody on the Host Defense Mechanism against Plasmodium yoelii yoelii Infection.

Abstract

ABSTRACT. Our previous reports indicated that C57BL/6 mice infected with a lethal variant of Plasmodium yoelii 17X (P. yoelii 17XL) produced high levels of interleukin 10 (IL-10) and interferon-γ (IFN-γ) while mice infected with the nonlethal variant of the parasite did not produce detectable levels of IL-10. In the present study, the involvement of IL-10 and IFN-γ in exacerbation or regulation of bloodstage malaria was investigated by using the lethal variant of P. yoelii 17XL and monoclonal antibodies (mAb) against the cytokines. C57BL/6 mice were injected intraperitoneally with a neutralizing anti-IL-10 mAb or anti-IFN-γ mAb after inoculation with P. yoelii 17XL. Treatment of mice with anti-IL-10 mAb resulted in substantial prolongation of survival and 60% of treated mice survived while 100% of control mice died by day 11. On the contrary, treatment of mice with anti-IFN-γ mAb exacerbated infection and all mice died after an earlier period than those treated with normal rat Ig. No differences in parasitemias were found between treated and untreated mice. To elucidate the involvement of nitric oxide in the host protection or exacerbation, mice were treated with aminoguanidine, an inhibitor of nitric oxide synthetase, after inoculation of P. yoelii 17XL. Neither mortality nor parasitemia was influenced by the treatment. These results indicate that an IFN-γ response is associated with protective immunity in mice infected with P. yoelii 17XL, while an IL-10

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

“…Despite clear evidence that anti-inflammatory cytokines and/or regulatory T cells inhibit the clearance of PyL pRBC (15,16,21,22,35,36), this study has not shown any role for T cells, NK cells, or IFN-␥ in the control of acute P. yoelii infection. However, given the absence of MHC expression on the majority of red blood cells (19), it is probable that neither T cells nor NK cells play the terminal effector role in parasite killing.…”

“…In contrast, IFN-␥ Ϫ/Ϫ mice on a C57BL/6 ϫ 129 background were unable to clear PyNL infections (56). Moreover, recombinant IFN-␥ protected SW, BALB/c, and CBA mice against PyL infection (47), and mice treated with anti-IFN-␥ antibodies succumbed earlier to lethal P. yoelii infection but had parasite levels similar to those of control mice (21). These results suggest that the lack of an early NK/IFN-␥ response in PyL-infected mice may impair parasite control.…”

“…It is clear that virulent and avirulent strains of P. yoelii differ in their ability to invade mature red blood cells (60,63), and this has recently been linked to differential copy number and expression patterns of genes putatively involved in erythrocyte invasion (1,18,41). Nevertheless, numerous studies from different laboratories have observed immunological differences between the two infections, including disparate IFN-␥ production, regulatory cytokine production, regulatory T-cell activation, and stromal cell activation (6,10,15,16,21,22,35,36,47,62), indicating that the virulence of P. yoelii parasites is not simply due to their erythrocyte invasion capacity. Significantly, our observation that clodronate liposome depletion of macrophages (58) results in more rapid growth of both PyL and PyNL parasites and more rapid onset of anemia indicates that macrophages play a major role in limiting the acute phase of P. yoelii infection.…”

“…After several days (around 5 days in mice), IFN-␥ from ␣␤ T cells begins to dominate the response. It has been reported that NK cell-derived IFN-␥ contributes to the early control of Plasmodium chabaudi, Plasmodium berghei, and Plasmodium yoelii infections (6,10,21,30,31) and that NK cell depletion enhances the virulence of nonlethal P. yoelii and P. chabaudi infections (6,20,31), although the latter finding has recently been debated (42). Conversely, ␥␦ T cells play only a minor role in the control of the acute primary wave of malaria infection, as TCR␥␦ Ϫ/Ϫ or ␥␦ T-cell-depleted mice develop comparable peak parasitemia with little or no delay in parasite clearance (24,43).…”

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…The initial pro-inflammatory response may switch to a predominant anti-inflammatory response that is mediated by immunoregulatory cytokines, such as TGF-β and IL-10 which down-regulate proinflammatory cytokine production to avoid malaria-associated pathology (7)(8)(9)(10)(11)(12). The pro-and anti-inflammatory cytokine balance is critical in determining the outcome of malaria infection (12)(13)(14)(15).…”