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<!-- EDIT BELOW THIS LINE Immunity

Protective immunity develops either after successful treatment of VL (cured) or after asymptomatic infections that resolve without development of VL

}}. Both types of immunity are characterized by CMI including skin test positivity, proliferation, and IL-2 (supports T cell proliferation) and IFN-g (activates macrophages to kill intracellular pathogens) secretion by PBMC in response to Leishmania antigens(ref Carvalho JID 1992,JI 1994,P-M 2005). T cells isolated from both cured and asymptomatic PBMC activate autologous macrophages to kill intracelluar Leishmania amastigotes (Holaday 1993a). Cured PBMC generally secreted less IFN-g and IL-5 and more IL-10 in response to Leishmania antigens than asymptomatic PBMC. T cells isolated from cured PBMC usually did not secrete IFN-g while activating autologous macrophages to kill intracellular amastigotes while T cells from asymptomatic PBMC always did. IL-12, important in the development and maintenance of T1 immune responses and IFN-g production, is involved in protective immunity. Addition of IL-12 to some VL PBMC increased proliferation and IFN-g secretion in response to leishmania antigens (Bacellar JID 1996, Holaday 1999). Anti-IL-12, added to cured PBMC, decreased leishmania specific proliferation and IFN-g secretion (ref). The ability of anti-IL-10 to increase IFN-g secretion was blocked by anti-IL-12 (ref). IL-17 is also associated with protective immunity (ref).

Leishmania antigen stimulation of PBMC from cured patients showed three types of responses, T1 only, T2 only, or T regulatory (ref Kemp CExpI 1999). Both CD4+ and CD8+ T cells contributed to IFN-g production (ref Saha JI 2007, P-M CexpI 2006, Gautam JID 2014). Studies of Leishmania antigen specific T cell clones from cured patient PBMC confirm that cured patients have a mixed T cell response that involves both CD4+ and CD8+ T cells. One study found clones that were CD4+ and were T1 only, T2 only, T1/T2, or none of these ref Kemp II 1993). A second study revealed that T cell clones from three of five cured patients had a T1 profile (refMary II 1999). Clones from a fourth cured patient had a T2 profile. Clones from a fifth patient had the same profile as those from asymptomatic subjects. A third study found both CD4+ and CD8+ regulatory T cell clones (Holaday 2000). The CD4+ clones secreted IL-10 in response to Leishmania antigens but the CD8+ clones secreted IL-10 in response to autologous irradiated PBMC alone and secreted less IL-10 when Leishmania antigen was added. Two studies of asymptomatic T cell clones showed that most had T1 profiles and secreted more IFN-g than T cell clones from cured patients. Neither study revealed the presence of T2 or regulatory T cells. One study found clones that were mostly CD4+, had a T1 profile, and activated autologous macrophages to kill intracellular amastigotes during which they secreted IFN-g (Holaday 1993b). The clones also secreted soluble factors that caused death of CD8+ regulatory T cells but not CD4+ T cells from VL patients (Holaday 2000). The second study found that many of their clones were CD8+ and had a T1 profile Mary). Their CD4+ clones had similar cytokine profiles but some also secreted high amounts of IL-5.

VL patients are unable to clear their infections because they lack CMI. This anergy may be limited to leishmania antigens or extend to mitogens and other antigens (refs choose). In addition to skin test negativity, VL patient PBMC do not proliferate or secrete IL-2 or IFN-g in response to leishmania antigens. Memory T cells maybe depleted in VL patient PBMC (ref Cilliari, Clarencio, Hailu). Elevated levels of IL-10 in the plasma and infected tissues of VL patients accompany the anergy (Holaday 1993b, Karp JCI 1993, Ghalib JCI 1993, P-M 2005). PKDL patients aso have elevated IL-10 levels. Since IL-10 is known to supress innate and acquired immunity and prevent IFN-g from activating macrophages, its role in VL has been studied extensively (ref de Waal JEM 1991, Oswald PNAS 1992). VL patients with the highest IL-10 levels were more likely to be unresponsive to treatment and progress to PKDL (ref Nylen JEM 2007, Gasim CEI 1998). Leishmania antigen stimulation of whole blood increased the number of IL-10+ monocytes while the number of IL-12+ and IFN-g+ leukocytes decreased (P-M 2005). PBMC from some VL patients secreted IL-10 without the addition of Leishmania antigen (endogenous) or in response to Leishmania antigen (Holaday 1993 b, 1999,). Levels of endogenous IL-10 secretion by VL PBMC was inversely correlated with Leishmania antigen specific IFN-g secretion (corr = -0.77) but Leishmania antigen specific IL-10 and IFN-g secretion were not correlated (corr = - 0.04) (ref Holaday 2000). When high endogenous IL-10 secretion occurred, addition of Leishmania antigen decreased it. Addition of anti-IL-10 increased proliferation and IFN-g secretion by PBMC from some patients ?, Holaday 1999). Both CD4+ and CD8+ T cells have been shown to contribute to IL-10 secretion by VL PBMC (Saha JI 2007).

Suppression of CMI during VL and PKDL maybe mediated by regulatory T cells and B cells (ref Rosser I 2015, Belkaid Nature 2007). CD4+ T regs were present at increased frequency in the bone marrow of VL patients, were one source of IL-10, and proliferated in response to Leishmania antigen (ref PLOS). Levels of FoxP3 mRNA were also upregulated in lesional tissue from PKDL patients (ref). However, Tregs were not elevated in spleen cells from VL patients nor did depletion of Tregs increase Leishmania antigen specific IFN-g secretion (Nylen). The highest levels of IL-10 mRNA in spleen cells was in CD8+ and other non-FoxP3+ T cells (Gautam. Blood leukocyte CD8+ T cells from VL patients had elevated IL-10 levels. )(P-M 2006). There was a 9.6 fold increase in IL-10 expressing CD8+ T cells among PBMC lymphocytes from PKDL patients. (ref) T cell clones isolated from VL PBMC were 100% CD8+ (Holaday 1993b). When mixed with autologous PBMC one or three years after successful treatment the CD8+ T cells decreased Leishmania antigen specific proliferation and IFN-g secretion and increased IL-10 secretion. Addition of anti-IL-10 restored IFN-g secretion. When CD8+ T cells from VL patients caused endogenous IL-10 secretion, addition of Leishmania antigen decreased the level, the same as it did for high endogenous IL-10 secretion by PBMC from VL patients. Depletion of CD8+ Tcells from VL PBMC completely ablated endogenous IL-10 secretion but increased Leishmania antigen specific IL-10 secretion, again suggesting that CD8+ regulatory T cells are responsible for endogenous IL-10 secretion.(Holaday 1993b, 2000) CD4+ clones could only be isolated from VL PBMC after CD8+ T cell depletion. The CD4+ clones showed that they had little effect on IL-10 secretion but decreased IFN-g secretion when mixed with autologous PBMC collected after successful treatment.

B regulatory cells are known to favor development of regulatory T cells and suppress development of T1 effector cells by producing IL-10 and other downregulatory cytokines. (Rosser)Il-10 levels were elevated in B cells from VL PBMC (P-M 2006). Studies of dogs with naturally acquired VL have shown that the percentage of regulatory B cells increased three-fold during VL (ref Schaut JI 2016). Depletion of B cells increased CD4+ T cell proliferation and IFN-g secretion but decreased IL-10 secretion. Blocking IL-10 receptors on B cells increased Leishmania antigen specific T cell proliferation and IFN-g secretion. Co-culture of T cells with B cells decreased the percentage CD4+ T cell of proliferation and IFN-g secretion CD4+ four-fold.

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IL-17

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Gautam 2016

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Anti-IL-10 refs

Belkaid Y. Regulatory T Cells and Infection: a Dangerous Necessity. Nature Rev Immunol 2007; 7: 875-88.

Rosser

Rai AK, Chandreshvar PT, Singh A, Seth T, Srivastava SK, Singh P, Mitra DK. Regulatory T Cells Sppress T Cell Activation at thr Pathologic Site in Human Visceral Leishmaniasis. PLOS One 2012:1-7, e31551.

Ganguly et al Enhanced Lesional FoxP3 Expression and Peripheral Anergic Lymphocytes Indicate a Role for Regulatory T Cells in Indian Post-Kala-azar Dermal Leishmaniasis. J Invest Dermatol 2010; 130: 1013-22.

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