Reconstitution of C.B‐17 scid mice with BALB/c T cells initiates a T helper type‐1 response and renders them capable of healing Leishmania major infection

Abstract

C.B-17 scid mice, which were found to be very susceptible to infection with Leishmania major, were reconstituted with various doses of T cells, T plus B cells or unfractionated spleen cells from nonhealer BALB/c mice. All reconstitution protocols, except for the transfer of very high numbers of BALB/c spleen cells, led to a spontaneously healing infection and resistance to reinfection, rather than the lethal, nonhealing infection typical of BALB/c mice. These healing responses were associated with a strong T helper 1 (Th1)-like response characterized by delayed-type hypersensitivity (DTH) responsiveness, but no elevation of serum IgE, and by the production of high levels of interferon-gamma (IFN-gamma), but no interleukin-4 (IL-4) by lymph node and spleen cells after restimulation with antigen in vitro. The development of this Th1 response from BALB/c Th cells requires IFN-gamma during the initial infection period. Treatment of scid mice with a single injection of neutralizing anti-IFN-gamma antibody prior to infection and reconstitution prevented healing and permitted the development of a Th-2 like response as indicated by elevated serum IgE, but no DTH, and by the production of IL-4, but very little IFN-gamma, after antigen stimulation in vitro. As few as 10(4) transferred T cells led to a Th1-like response, suggesting that the IFN-gamma is of host rather than donor origin. The transfer of very high numbers (7.5 x 10(7)) of BALB/c spleen cells overcame the effects of the IFN-gamma and led to the nonhealing infection and cytokine pattern characteristic of BALB/c mice. The enrichment or depletion of B cells from the transferred T cells had no measurable effect upon the development of a healing response in reconstituted scid mice.

CD4+Cells Are Indispensable for Ulcer Development in Murine Cutaneous Leishmaniasis

“…The formation of nonulcerative nodules in SCID mice after the infection with L. amazonensis is consistent with previous reports using L. major (7,23) and suggests that ulcer formation in cutaneous nodules in leishmaniasis is a lymphocyte-dependent reaction. Therefore, we investigated lymphocyte subsets which might play pivotal roles in ulcer formation using a SCID mouse model.…”

“…Therefore, we investigated lymphocyte subsets which might play pivotal roles in ulcer formation using a SCID mouse model. Previous work using SCID mice has shown the relative ease of reconstitution of the immune system with immunocompetent splenocytes containing functional T and B cells (23). Hence, we examined the ability of immunocompetent splenocytes to induce ulcer formation in cutaneous leishmaniasis lesions by transferring them into L. amazonensis-infected SCID mice.…”

Inbred Strains Derived from Feral Mice Reveal New Pathogenic Mechanisms of Experimental Leishmaniasis Due toLeishmania major

“…This model has been instrumental in the in vivo validation of the functional dichotomy of CD4 ϩ T-helper cells and their involvement in determining the outcome of disease (34,48,54). Thus, resistant C57BL/6 mice infected with L. major develop a TH1 response resulting in gamma interferon (IFN-␥) production, macrophage activation, parasite killing, and resolution of the experimental lesion (19,36,55). In contrast, susceptible BALB/c mice mount a TH2 response and show macrophage deactivation leading to parasite dissemination and severe progressive disease (8,19,28,38).…”

In vitro and in vivo functional analysis of CD+ and CD5− B cells of autoimmune NZB ∨ NZW F1 mice

“…Potential use of SCID mice as an animal model for human diseases such as haematopoiesis and oncology has also been suggested. In murine models, SCID mice have also been applied to the study of infectious diseases and autoantibody-related acute graft-versus-host disease [35,36]. Previous study has already demonstrated that SCID mice can be used as an in vivo model for autoimmue disease with the reconstitution of spleen cells from NZB/W F 1 mice (data not shown).…”