The Immunology of a Healing Response in Cutaneous Leishmaniasis Treated with Localized Heat or Systemic Antimonial Therapy

Abstract

Background

The effectiveness of systemic antimonial (sodium stibogluconate, Pentostam, SSG) treatment versus local heat therapy (Thermomed) for cutaneous leishmaniasis was studied previously and showed similar healing rates. We hypothesized that different curative immune responses might develop with systemic and local treatment modalities.

Methods

We studied the peripheral blood immune cells in a cohort of 54 cutaneous Leishmania major subjects treated with SSG or TM. Multiparameter flow cytometry, lymphoproliferative assays and cytokine production were analyzed in order to investigate the differences in the immune responses of subjects before, on and after treatment.

Results

Healing cutaneous leishmaniasis lead to a significant decline in circulating T cells and NKT-like cells, accompanied by an expansion in NK cells, regardless of treatment modality. Functional changes involved decreased antigen specific CD4 ⁺ T cell proliferation (hyporesponsiveness) seen with CD8 ⁺ T cell depletion. Moreover, the healing (or healed) state was characterized by fewer circulating regulatory T cells, reduced IFN-γ production and an overall contraction in polyfunctional CD4 ⁺ T cells.

Conclusion

Healing from cutaneous Leishmaniasis is a dynamic process that alters circulating lymphocyte populations and subsets of T, NK and NKT-like cells. Immunology of healing, through local or systemic treatments, culminated in similar changes in frequency, quality, and antigen specific responsiveness with immunomodulation possibly via a CD8 ⁺ T cell dependent mechanism. Understanding the evolving immunologic changes during healing of human leishmaniasis informs protective immune mechanisms.

Author Summary

Globally, leishmaniasis treatment relies on the use of antimonial drugs (i.e. SSG). In an earlier study we showed that skin lesions due to L. major treated by the ThermoMed (TM) device healed at a similar rate and with less associated systemic toxicity than lesions treated with intravenous SSG. The current study compared the immune responses of these two therapeutic groups before, during and after therapy which may be relevant to resistance to reinfection and also in consideration for the development of local (versus systemic) therapy. Antimonials have immune effects on both the host and parasite while heat treatment locally kills the parasite and induces inflammation from a secondary burn. We demonstrated that healing from cutaneous leishmaniasis is a dynamic process associated with a modulation of immune responses independent of treatment modalities.