The chapter discusses the immunology of susceptibility and resistance to *Leishmania major* in mice, focusing on the role of T helper (Th) 1 and Th2 cytokines. It highlights the complexity of the Th1/Th2 balance in determining the outcome of *L. major* infection, with Th2-driven responses often leading to disease and Th1-driven responses promoting healing and parasite clearance. The text reviews recent findings that challenge the simplicity of this model, emphasizing the importance of other cytokines and immune mechanisms in both susceptibility and resistance. Key points include: 1. **T Helper 1/2 (Th1/Th2) Balance**: The Th1/Th2 balance is crucial in regulating disease outcomes. Th1 responses, driven by cytokines like interferon-γ (IFN-γ), are essential for parasite killing and healing, while Th2 responses, driven by cytokines like interleukin-4 (IL-4), promote antibody production and can lead to disease. 2. **Susceptibility in BALB/c Mice**: BALB/c mice are particularly susceptible to *L. major* due to their dominant Th2 response, which is driven by a small subset of CD4+ T cells that produce IL-4. However, recent studies suggest that the early production of IL-4 alone is not sufficient to cause susceptibility, and other factors, such as IL-13 and transforming growth factor-β (TGF-β), may also play roles. 3. **Resistant Mice**: In contrast, resistant mice, such as C57BL/6, develop a strong Th1 response, which is characterized by high levels of IFN-γ and tumor necrosis factor (TNF). These mice control the infection and generate long-lasting immunity. The text discusses the importance of IL-12 in redirecting the early Th2 response to a Th1 response, which is crucial for resistance. 4. **Cytokine Interactions**: The text explores the interactions between various cytokines, such as IL-4, IL-10, and IL-13, and their roles in susceptibility and resistance. For example, IL-10 can suppress Th1 responses and activate macrophages, while IL-13 can exacerbate infection. 5. **Effector Molecules and CD8+ T Cells**: The text also discusses the role of effector molecules like inducible nitric oxide synthase (iNOS) and the importance of CD8+ T cells in controlling primary and secondary infections. CD8+ T cells are crucial for the release of IFN-γ and the cytolysis of infected cells. 6. **Implications for Vaccine Design**: The findings have significant implications for vaccine development. Live vaccines, such as leishmanization, provide strong and long-lasting protection, while non-living vaccines often fail to induce adequate CD8+ T-cell responses. TheThe chapter discusses the immunology of susceptibility and resistance to *Leishmania major* in mice, focusing on the role of T helper (Th) 1 and Th2 cytokines. It highlights the complexity of the Th1/Th2 balance in determining the outcome of *L. major* infection, with Th2-driven responses often leading to disease and Th1-driven responses promoting healing and parasite clearance. The text reviews recent findings that challenge the simplicity of this model, emphasizing the importance of other cytokines and immune mechanisms in both susceptibility and resistance. Key points include: 1. **T Helper 1/2 (Th1/Th2) Balance**: The Th1/Th2 balance is crucial in regulating disease outcomes. Th1 responses, driven by cytokines like interferon-γ (IFN-γ), are essential for parasite killing and healing, while Th2 responses, driven by cytokines like interleukin-4 (IL-4), promote antibody production and can lead to disease. 2. **Susceptibility in BALB/c Mice**: BALB/c mice are particularly susceptible to *L. major* due to their dominant Th2 response, which is driven by a small subset of CD4+ T cells that produce IL-4. However, recent studies suggest that the early production of IL-4 alone is not sufficient to cause susceptibility, and other factors, such as IL-13 and transforming growth factor-β (TGF-β), may also play roles. 3. **Resistant Mice**: In contrast, resistant mice, such as C57BL/6, develop a strong Th1 response, which is characterized by high levels of IFN-γ and tumor necrosis factor (TNF). These mice control the infection and generate long-lasting immunity. The text discusses the importance of IL-12 in redirecting the early Th2 response to a Th1 response, which is crucial for resistance. 4. **Cytokine Interactions**: The text explores the interactions between various cytokines, such as IL-4, IL-10, and IL-13, and their roles in susceptibility and resistance. For example, IL-10 can suppress Th1 responses and activate macrophages, while IL-13 can exacerbate infection. 5. **Effector Molecules and CD8+ T Cells**: The text also discusses the role of effector molecules like inducible nitric oxide synthase (iNOS) and the importance of CD8+ T cells in controlling primary and secondary infections. CD8+ T cells are crucial for the release of IFN-γ and the cytolysis of infected cells. 6. **Implications for Vaccine Design**: The findings have significant implications for vaccine development. Live vaccines, such as leishmanization, provide strong and long-lasting protection, while non-living vaccines often fail to induce adequate CD8+ T-cell responses. The