David J. Wyler

Intravascular Clearance of Parasitized Erythrocytes in Rodent Malaria

Little is known about host defense mechanisms responsible for protective immunity in malaria. The intravascular location of the infection suggested that removal of parasitized erythrocytes by reticuloendothelial organs might be important. To study this possibility, we examined the clearance of (51)Crlabeled Plasmodium berghei-infected erythrocytes in rats. Infected erythrocytes were removed more rapidly from circulation than homologous uninfected erythrocytes. The rate of clearance of infected cells during the 1st hour after inoculation was approximately three times greater in rats rendered immune by prior infection than in control rats. This accelerated clearance resulted from greater splenic uptake in immune rats and appeared to correlate with spleen size. Since the clearance pattern of infected erythrocytes more closely resembled the clearance of Heinz body-containing uninfected erythrocytes than of antibody-coated (immunoglobulin G) uninfected erythrocytes, rheologic alterations of parasitized erythrocytes might be a more important determinant of clearance than an antibody-dependent process. During the phase of malaria infection in which increasing parasitemia is observed, organ uptake of infected erythrocytes did not increase despite splenic and hepatic enlargement. However during the spontaneous onset of resolution of malaria infection characterized by decreasing parasitemia, a marked enhancement of splenic clearance was noted. These observations suggest that sudden alteration in splenic clearance of parasitized erythrocytes might be important in the resolution of acute malaria.

Relationship of alterations in splenic clearance function and microcirculation to host defense in acute rodent malaria.

During the course of Plasmodium berghei malaria in the rat, splenic clearance of damaged uninfected erythrocytes (heated or Heinz body-containing) underwent changes strikingly similar to those of infected erythrocytes. Splenic trapping of abnormal erythrocytes was impaired during the period of rising parasitemia but became supernormal just before the onset of resolution of the acute infection. These changes could be related to the development of splenomegaly and alterations in splenic cordal microcirculation during infection. The relative distribution of flow through the cords was decreased during rising parasitemia and was restored before the onset of resolution. Together, our observations support the hypothesis that altered rheologic properties of infected erythrocytes are a major determinant of their removal by the spleen. These data suggest that the alterations in splenic microcirculation that occur during malaria may have important implications for host defense.

Circulating factor from a kala-azar patient suppresses in vitro antileishmanial T cell proliferation

In vitro lymphocyte blastogenesis stimulated by phytohaemagglutinin (PHA), streptococcal antigens (SKSD) and leishmanial antigens were used to assess T cell responsiveness in one patient with kala-azar before and after therapy. During the illness, responses to PHA and SKSD but not to leishmanial antigens could be detected. After treatment lymphocytes responded to all three stimuli when cells were cultured in convalescent plasma, but failed to respond to leishmanial antigens when cultured in plasma obtained before treatment. These observations suggest the presence of a circulating inhibitor of anti-leishmanial T cell responsiveness in kala-azar, and warrant further investigation.