TRANSFORMING-GROWTH-FACTOR-BETA PRODUCTION IS INVERSELY CORRELATED WITH SEVERITY OF MURINE MALARIA INFECTION

We have examined the role of the immunomodulatory cytokine transformin g growth factor (TGF)-beta in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-beta, and production of bioa ctive TGF-beta by splenocytes, were found to be low in lethal injectio ns with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-bet a production. A causal association between the failure to produce TGF- beta and the severity of malaria injection was demonstrated by treatme nt of infected mice with neutralizing antibody to TGF-beta, which exac erbated the virulence of P. berghei and transformed a resolving P. cha baudi chabaudi infection into a lethal infection, but had little effec t on the course of P. yoelii infection. Parasitemia increased more rap idly in anti-TGF-beta-treated mice but this did not seem to be the exp lanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei-infected mice with recombinan t TGF-beta (rTGF-beta) slowed the rate of parasite proliferation and p rolonged their survival from 15 to up to 35 d. rTGF-beta treatment was accompanied by a significant decrease in serum tumor necrosis factor a and an increase in interleukin 10. Finally, we present evidence that differences in TGF-beta responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-beta. Thus, TGF-beta seems t o induce protective immune responses, leading to slower parasite growt h, early in infection, and, subsequently, appears to downregulate path ogenic responses late in infection. This duality of effect makes TGF-b eta a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.