Role of cytokines in resistance to African trypanosomes

The expression and role of cytokines in resistance to experimental Trypanosoma congolense infections in the highly susceptible BALB/c and relatively resistant C57BL/6 mice was studied. Higher levels of IL-4, IL-10 and IFN-ã were detected in the plasma of infected BALB/c than in C57BL/6 mice. In contrast, plasma levels of TNF-á were higher in C57BL/6 than in BALB/c mice. IL-10 and IFN-ã mRNA transcripts accumulated earlier and in higher concentrations in the spleens of susceptible than in resistant mice. TNF-á mRNA levels in the spleens were similar, but the hepatic TNF-á mRNA levels were higher in resistant than in susceptible mice on day 9. The kinetics of IL-4, IL-10 and IFN-ã spot-forming cells in the spleens were essentially similar but significantly higher numbers were detected in BALB/c than in C57BL/6 mice. Unstimulated and concanavalin A (Con A)-stimulated splenocytes from BALB/c mice secreted high amounts of IL-4, IL-10 and IFN-ã in cultures starting from day 4. Secretion of IL-4 by splenocytes from infected C57BL/6 mice was undetectable throughout the period tested. Secretion of IL-10 and IFN-ã became appreciable on day 6 but were down regulated by day 8. Treatment of infected BALB/c mice with Berenil resulted in cure and caused a dramatic decline in the secretion of IL-10 and IFN-ã by BALB/c splenocytes. Con A-induced proliferation of splenocytes from infected BALB/c mice was progressively suppressed. Anti-IL-10 or anti-IFN-ã antibodies effectively reversed this suppression. Whereas in vivo administrations of anti-IL-10 antibodies to BALB/c mice early during infection only moderately prolonged their survival period, anti-IFN-ã antibodies shifted the phenotype of susceptible BALB/c mice to a resistant-like phenotype. Most of the IL-4, IL-10 and IFN-ã found in the infected BALB/c mice were produced by adherent Thy1.2\sp+CD4\sp-8\sp- splenocytes in synergy with adherent Thy1.2\sp- cells. These adherent cells suppressed T and B cell responses. Infected BALB/c mice mounted an earlier IgM response to various antigens of T. congolense than did C57BL/6 mice. In contrast, C57BL/6 mice made a strong and sustained IgG2a and IgG3 response to these antigens. It is hypothesized that resistance to T. congolense infection in mice is mediated by a TH1 cell response

Protective Immunity and Vaccination Against Cutaneous Leishmaniasis

Although a great deal of knowledge has been gained from studies on the immunobiology of leishmaniasis, there is still no universally acceptable, safe, and effective vaccine against the disease. This strongly suggests that we still do not completely understand the factors that control and/or regulate the development and sustenance of anti-Leishmania immunity, particularly those associated with secondary (memory) immunity. Such an understanding is critically important for designing safe, effective, and universally acceptable vaccine against the disease. Here we review the literature on the correlate of protective anti-Leishmania immunity and vaccination strategies against leishmaniasis with a bias emphasis on experimental cutaneous leishmaniasis

Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose–infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon γ–producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response

The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells

The distinction between innate and adaptive immunity is one of the basic tenets of immunology. The co-operation between these two arms of the immune system is a major determinant of the resistance or susceptibility of the host following pathogen invasion. Hence, this interactive co-operation between cells of the innate and adaptive immunity is of significant interest to immunologists. The sub-population of CD4+ T cells with regulatory phenotype (regulatory T cells; Tregs), which constitute a part of the adaptive immune system, have been widely implicated in the regulation of the immune system and maintenance of immune homeostasis. In the last two decades, there has been an explosion in research describing the role of Tregs and their relevance in several immunopathologies ranging from inflammation to cancer. The majority of these studies focus on the role of Tregs on the cells of the adaptive immune system. Recently, there is significant interest in the role of Tregs on cells of the innate immune system. In this review, we examine the literature on the role of Tregs in immunology. Specifically, we focus on the emerging knowledge of Treg interaction with dendritic cells, macrophages, neutrophils, and γδ T cells. We highlight this interaction as an important link between innate and adaptive immune systems which also indicate the far-reaching role of Tregs in the regulation of immune responses and maintenance of self-tolerance and immune homeostasis

Deficiency of Leishmania phosphoglycans influences the magnitude but does not affect the quality of secondary (memory) anti-Leishmania immunity

Despite inducing very low IFN-γ response and highly attenuated in vivo, infection of mice with phosphoglycan (PG) deficient Leishmania major (lpg2-) induces protection against virulent L. major challenge. Here, we show that mice infected with lpg2- L. major generate Leishmania-specific memory T cells. However, in vitro and in vivo proliferation, IL-10 and IFN-γ production by lpg2- induced memory cells were impaired in comparison to those induced by wild type (WT) parasites. Interestingly, TNF recall response was comparable to WT infected mice. Despite the impaired proliferation and IFN-γ response, lpg2- infected mice were protected against virulent L. major challenge and their T cells mediated efficient infection-induced immunity. In vivo depletion and neutralization studies with mAbs demonstrated that lpg2- L. major-induced resistance was strongly dependent on IFN-γ, but independent of TNF and CD8(+) T cells. Collectively, these data show that the effectiveness of secondary anti-Leishmania immunity depends on the quality (and not the magnitude) of IFN-γ response. These observations provide further support for consideration of lpg2- L. major as a live-attenuated candidate for leishmanization in humans since it protects strongly against virulent challenge, without inducing pathology in infected animals

Thymic Stromal Lymphopoietin Is Critical for Regulation of Proinflammatory Cytokine Response and Resistance to Experimental Trypanosoma congolense Infection

African trypanosomiasis (sleeping sickness) poses serious threat to human and animal health in sub-Saharan Africa. Because there is currently no vaccine for preventing this disease and available drugs are not safe, understanding the mechanisms that regulate resistance and/or susceptibility to the disease could reveal novel targets for effective disease therapy and prevention. Thymic stromal lymphopoietin (TSLP) plays a critical role in driving Th2 immune response. Although susceptibility to experimental Trypanosoma congolense infection in mice is associated with excessive proinflammatory responses due in part to impaired Th2 response, the role of TSLP in resistance to African trypanosomiasis has not been well studied. Here, we investigated whether TSLP is critical for maintaining Th2 environment necessary for survival of T. congolense-infected mice. We observed an increased TSLP level in mice after infection with T. congolense, suggesting a role for this cytokine in resistance to the infection. Indeed, TSLPR−/− mice were more susceptible to T. congolense infection and died significantly earlier than their wild-type (WT) controls. Interestingly, serum levels of IFN-γ and TNF-α and the frequency of IFN-γ- and TNF-α-producing CD4+ T cells in the spleens and liver were significantly higher in infected TSLPR−/− mice than in the WT control mice. Susceptibility was also associated with excessive M1 macrophage activation. Treatment of TSLPR−/− mice with anti-IFN-γ mAb during infection abolished their enhanced susceptibility to T. congolense infection. Collectively, our study shows that TSLP plays a critical role in resistance to T. congolense infection by dampening the production of proinflammatory cytokines and its associated M1 macrophage activation

The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response

The complicated interactions between Leishmania and the host antigen-presenting cells (APCs) have fundamental effects on the final outcome of the disease. Two major APCs, macrophages and dendritic cells (DCs), play critical roles in mediating resistance and susceptibility during Leishmania infection. Macrophages are the primary resident cell for Leishmania: they phagocytose and permit parasite proliferation. However, these cells are also the major effector cells to eliminate infection. The effective clearance of parasites by macrophages depends on activation of appropriate immune response, which is usually initiated by dendritic cells. Here, we review the early interaction of APCs with Leishmania parasites and how these interactions profoundly impact on the ensuing adaptive immune response. We also discuss how the current knowledge will allow further refinement of our understanding of the interplay between Leishmania and its hosts that leads to resistance or susceptibility

Regulation of Immunity in Breast Cancer

Breast cancer affects millions of women worldwide, leading to many deaths and significant economic burden. Although there are numerous treatment options available, the huge potentials of immunotherapy in the management of localized and metastatic breast cancer is currently being explored. However, there are significant gaps in understanding the complex interactions between the immune system and breast cancer. The immune system can be pro-tumorigenic and anti-tumorigenic depending on the cells involved and the conditions of the tumor microenvironment. In this review, we discuss current knowledge of breast cancer, including treatment options. We also give a brief overview of the immune system and comprehensively highlight the roles of different cells of the immune system in breast tumorigenesis, including recent research discoveries. Lastly, we discuss some immunotherapeutic strategies for the management of breast cancer

Host intracellular signaling events and pro-inflammatory cytokine production in African trypanosomiasis

Pathogens such as bacteria, viruses and parasites possess specific molecules or proteins that are recognized by several host innate immune receptors leading to the activation of several intracellular signaling molecules and pathways. The magnitude and quality of these events significantly affect the outcome of infection. African trypanosomes, including Trypanosoma congolense, are capable of manipulating the host immune response, including the activity of macrophages, which are key immune cells that contribute to the immunopathogenesis of African trypanosomiasis. Although it is known that immune hyperactivation and excessive proinflammatory cytokine production are hallmarks of African trypanosomiasis, the mechanisms through which these events are triggered are poorly defined. However, it is known that macrophages may play a significant role in these processes because phagocytosis of trypanosomes by macrophages initiates intracellular signal transduction cascades that lead to release of proinflammatory cytokines and alteration in cell function. This review highlights recent progress in our understanding of the innate immune receptors, signaling pathways and transcription factors involved in T. congolense-induced pro-inflammatory cytokine production in by macrophages. It will reveal the existence of complex signaling events through which the parasite modulates the host immune response thus identifying novel targets that could aid in designing strategies to effectively control the disease