Resistance to the African trypanosomes is IFN-gamma dependent.

The role of variant surface glycoprotein (VSG)-specific Th cell responses in determining resistance to the African trypanosomes was examined by comparing Th cell responses in relatively resistant and susceptible mice as well as in cytokine gene knockout mice infected with Trypanosoma brucei rhodesiense. Resistant B10.BR and C57BL/6 mice expressed Th1 cell cytokine responses to VSG stimulation during infection, while susceptible C3H mice produced weak or no Th1 cell cytokine responses. Neither resistant B10.BR and C57BL/6 mice nor susceptible C3H mice made detectable Th2 cell cytokine responses to parasite Ag. To more closely examine the potential role of IFN-gamma and other cytokines in host resistance, we determined the resistance phenotypes and Th cell responses of IFN-gamma and IL-4 knockout mice. Infected C57BL/6-IFN-gamma knockout mice were as susceptible as C57BL/6-scid mice and made an IL-2, but not an IL-4, cytokine response to VSG, while C57BL/6-IL-4 knockout mice were as resistant as the wild-type strain and exhibited both IL-2 and IFN-gamma cytokine responses. Passive transfer of spleen cells from wild-type mice to IFN-gamma knockout mice resulted in enhanced survival. Both wild-type and IFN-gamma knockout mice controlled parasitemia with VSG-specific Ab responses, although parasitemias were higher in the IFN-gamma knockout mice. Overall, this study demonstrates for the first time that relative resistance to African trypanosomes is associated with a strong Th1 cell response to parasite Ags, that IFN-gamma, but not IL-4, is linked to host resistance, and that susceptible animals do not make compensatory Th2 cell responses in the absence of Th1 cell cytokine responses.

Hertz CJ ，Filutowicz H ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》

IFN-gamma-dependent nitric oxide production is not linked to resistance in experimental African trypanosomiasis.

Resistance to African trypanosomes is dependent on B cell and Th1 cell responses to the variant surface glycoprotein (VSG). While B cell responses to VSG control levels of parasitemia, the cytokine responses of Th1 cells to VSG appear to be linked to the control of parasites in extravascular tissues. We have recently shown that IFN-gamma knockout (IFN-gamma KO) mice are highly susceptible to infection and have reduced levels of macrophage activation compared to the wild-type C57BL/6 (WT) parent strain, even though parasitemias were controlled by VSG-specific antibody responses in both strains. In the present work, we examine the role of IFN-gamma in the induction of nitric oxide (NO) production and host resistance and in the development of suppressor macrophage activity in mice infected with Trypanosoma brucei rhodesiense. In contrast to WT mice, susceptible IFN-gamma KO mice did not produce NO during infection and did not develop suppressor macrophage activity, suggesting that NO might be linked to resistance but that suppressor cell activity was not associated with resistance or susceptibility to trypanosome infection. To further examine the consequence of inducible NO production in infection, we monitored survival, parasitemia, and Th cell cytokine production in iNOS KO mice. While survival times and parasitemia of iNOS KO mice did not differ significantly from WT mice, VSG-specific Th1 cells from iNOS KO mice produced higher levels of IFN-gamma and IL-2 than cells from WT mice. Together, these results show for the first time that inducible NO production is not the central defect associated with susceptibility of IFN-gamma KO mice to African trypanosomes, that IFNgamma-induced factors other than iNOS may be important for resistance to the trypanosomes, and that suppressor macrophage activity is not linked to either the resistance or the susceptibility phenotypes.

Hertz CJ ，Mansfield JM 《CELLULAR IMMUNOLOGY》

Genetics of resistance to the African trypanosomes. VI. Heredity of resistance and variable surface glycoprotein-specific immune responses.

The question of genetic linkage of parasite-specific immune responses to resistance to infection in experimental African trypanosomiasis was addressed. For this purpose, major histocompatibility complex-compatible resistant and susceptible inbred mouse strains and their F1 hybrid, F2 hybrid, and backcross offspring were infected with Trypanosoma brucei rhodesiense LouTat 1. Immunologic control of the first peak of parasitemia and survival times were the parameters measured. As we have reported previously (R. F. Levine and J. M. Mansfield, J. Immunol. 133:1564, 1984), B10.BR/SgSnJ mice are relatively resistant and controlled the growth of the infecting variant antigenic type (VAT) by mounting an antibody response to exposed epitopes of the variable surface glycoprotein (VSG). Fluctuating parasitemias resulting from sequential growth of different variable antigenic types occurred subsequently, and these mice died with a median survival time of 48 days. C3HeB/FeJ mice, relatively susceptible, did not control the infecting VAT and did not exhibit VSG-specific antibodies. These mice died with a median survival time of 22 days. The (B10.BR X C3H)F1 hybrids derived from crosses between resistant and susceptible mice all exhibited VSG-specific antibody responses and controlled the infecting VAT population. However, the median survival time of the F1 hybrids (24 days) was not significantly different from the survival time of the susceptible C3H parent. These findings demonstrate for the first time that antibody-mediated control of parasitemia is inherited as a dominant trait; that overall resistance, as measured by survival time, is inherited as a recessive trait (e.g., susceptibility is dominant); and that the two events segregate independently of one another. Further analyses of the inheritance of immunity and resistance (survival time) were made in which the F2 hybrid and backcross studies revealed that there are multiple genes controlling the VSG-specific antibody response as well as determining susceptibility. An extension of the present studies to a similar but non-major histocompatibility complex-mouse model system of resistance and susceptibility (C57BL/6J and C3H/HeJ mice, F1 hybrids, and 11 recombinant inbred B X H strains derived from them) was made in order to link the strain distribution patterns of known genetic markers with control of VSG-specific antibody responses or with control of susceptibility. Results of this study showed that resistance varied independently of the ability to control parasitemia with VSG-specific B cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)

De Gee AL ，Levine RF ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》

Control of parasitemia and survival during Trypanosoma brucei brucei infection is related to strain-dependent ability to produce IL-4.

We studied non-MHC gene-dependent expression of a number of cytokines in relation to host defense and survival during Trypanosoma brucei brucei (Tbb) infection in mice. In particular, the role of IL-4 was explored with use of genomically IL-4-disrupted mice and in vivo Ab blocking. Splenocytes from MHC-identical B10.Q (relatively resistant) mice showed day 5 postinfection higher numbers of IL-4 mRNA expressing cells than C3H.Q (highly susceptible). A trypanosome-derived lymphocyte triggering factor, which is released by Tbb to polyclonally activate CD8+ T cells, stimulated naive splenocytes in vitro to a higher IL-4 response in B10.Q than in C3H.Q mice. The C3H.Q mice developed an extremely high parasitemia, showed a low Ab response against the variant surface glycoprotein (VSG), and had a mean survival time of 42 days. Conversely, B10.Q mice had lower parasitemia, mounted higher anti-VSG response, and had a mean survival time of 56 days. Deletion of the IL-4 gene had no influence on the infection in C3H.Q mice, while in B10.Q mice the deletion was associated with lower anti-VSG Ab levels and higher parasitemia. Paradoxically, B10.Q mice with disrupted IL-4 gene survived longer than the wild type. Anti-IL-4 Ab-blocking experiments in vivo displayed an enhanced parasitemia and prolonged survival in infected B10.Q mice. We conclude that 1) a non-MHC gene-related and CD8+-dependent ability to produce IL-4 partly determines the susceptibility to Tbb infection; and 2) IL-4, although involved in controlling the levels of parasitemia by its effects on immunoglobulin synthesis, also can have toxic effects on the animals.

Bakhiet M ，Jansson L ，Büscher P ，Holmdahl R ，Kristensson K ，Olsson T ... -  《JOURNAL OF IMMUNOLOGY》

Genetics of resistance to the African trypanosomes. V. Qualitative and quantitative differences in interferon production among susceptible and resistant mouse strains.

The induction of interferon (IFN) was examined in different inbred mouse strains infected with Trypanosoma brucei rhodesiense. Relatively susceptible C3HeB/FeJ mice that do not exhibit variant-specific immunity or control parasitemia did not exhibit detectable IFN throughout the infection. Relatively resistant B10.BR mice that exhibit variant-specific immunity and control the first peak of parasitemia exhibited detectable IFN at two intervals. The appearance of IFN in B10.BR serum first coincided with the onset of the parasitemia 4 days after infection and then disappeared; this IFN peak was predominantly IFN-alpha/beta. The second time of appearance coincided with high titers of antibody and remission of the parasitemia. This IFN was predominantly IFN-gamma. Intermediately susceptible CBA/J mice also exhibited two detectable peaks of IFN; the first IFN-alpha/beta peak coincided with the onset of the parasitemia as in B10.BR mice. The second peak of IFN in the serum of CBA mice, however, was delayed in appearance and lower in concentration compared with B10.BR mice. This peak was characterized as being predominantly IFN alpha/beta. BALB/c mice (also intermediately susceptible) did not exhibit a first peak of IFN-alpha/beta production, but the second peak of IFN-alpha/beta production was similar to that seen in CBA mice. In contrast to infected mice, IFN was induced in both susceptible (C3H) and resistant (B10.BR) mice after immunization with glutaraldehyde-fixed trypanosomes or after chemotherapy of infection. We conclude that both the levels of IFN as well as the type of IFN induced during infection with T. b. rhodesiense depend upon the genetic background of the mouse strain infected. The induction of IFN-gamma in mice of the C57BL background may be linked functionally to more effective parasite control and to the presence of an effective immune response to T. b. rhodesiense.

de Gee AL ，Sonnenfeld G ，Mansfield JM 《JOURNAL OF IMMUNOLOGY》