These cytokines are involved in the development of Th1 dominated immune responses, which in context of VL is associated with disease suppression. Our data showed that lipoCpG-ODN-2006 in combination with short dose of miltefosine has immense potential to skew Th2 type immune responses generated by Leishmania infection in hamsters towards hostprotective Th1 response. IFN-c, a hallmark Th1 cytokine was found to be significantly elevated in lipo-CpG-ODN-2006 plus sub-curative miltefosine treated animals along with IL-12. The synergistic stimulation of IL-12 with IFN-c might provide a better additive effect for clearance of Leishmania parasite. The level of TNF-a mRNA expression was also increased in the group of animals treated with lipo-CpG-ODN-2006 plus miltefosine. VL progression is associated with induction of Th2- dominated immune responses in which, IL-10 has been demonstrated to antagonize Th1 driven cytokines, IL-12 and IFN-c thereby blocking iNOS expression. Along with IL-10, TGF-b also suppresses macrophage activation and generation of NO. In line with this, our observation revealed that mRNA expression level of both Th2 cytokines, IL-10 and TGF-b, were downregulated at both the time points in treated animals. The highest suppression of these cytokines was found to lipo-CpG-ODN-2006 plus sub-curative miltefosine treated group. Moreover, overall skewing of CD4 + T-cell differentiation in Th1 mode in infected animals, which undergo combination therapy with lipo-CpGODN-2006 plus miltefosine, has been further reflected in heightened expression of iNOS and generation of NO. This also supports the view regarding the up-regulation of iNOS by Th1 cell associated cytokines and confirms that NO-mediated macrophage effector mechanism is critical for controlling the parasites in the animal model. Disease severity in experimental visceral leishmaniasis was associated with significantly hampered antigen presentation and antigen-specific T cell activation in murine and hamster models and elicitation of effective T-cell based host immune response defines the success of antileishmanial chemotherapeutics. In our study, enhanced antigen specific expansion of T-cell repertoire in all treated group of animals were observed with maximum induction in lipo-ODN-2006 and miltefosine. This might be account for skewing the T-cell repertoire towards a Th1 type phenotype as substantiated by the elevated level of IFN-c, IL-12 and TNF-a mRNA transcript in splenocytes derived from all treated group of hamsters and mice. Apart from liver and spleen, the involvement of lymph nodes has been well documented in clinical cases of leishmaniasis as well as in experimental animals in the form of lymphadenopathy with occasional demonstration of leishmanial parasites. However, few studies in Leishmania infected experimental models have been conducted on lymph node involvement and the fate of lymph nodes during disease progression.