Avaliação de Mimotopos selecionados por Phage Display como Agentes Imunoterápicos contra as Leishmanioses

Abstract

Leishmaniasis can cause several clinical manifestations in mammalian hosts, which are influenced by the parasite species and the immune status of the infected host. Due to the limitations of current treatment, such as toxicity, high cost and therapeutic failure; there is an urgent need to develop new forms of therapy. The development of alternative and low-cost therapeutic strategies, especially immunotherapy, has been sought in leishmaniasis. This approach seeks to eliminate the parasite by means of an antileishmanial drug and induce the development of a protective immune response against reinfection. With the advancement of biotechnology tools, techniques such as Phage display have been used in the identification of new antigens and in the discovery of diagnostic markers and vaccine candidates. In this study, Phage display was used to select mimotopes for use in immunotherapy against visceral leishmaniasis (VL) caused by Leishmania infantum and cutaneous leishmaniasis (CL) caused by L. amazonensis in a murine model. Four mimotopes (phage clones) were used, two of them for VL and two for CL. Phages A4 and A8 were combined with amphotericin B (AmpB) and evaluated alone or in combination for the treatment of CL, showing efficacy in controlling infection and cure. The combinations A4/AmpB and A8/AmpB induced a specific Th1-type immune response, resulting in a significant reduction in lesion diameter and parasite load, in addition to decreasing drug toxicity. For VL, phages B1 and D11 were selected and used alone or in combination with AmpB, and it was observed that the combinations B1/AmpB and D11/AmpB induced also a better Th1-type immune response, with high levels of IFN-γ, IL-12, TNF-α and nitrite, in addition to significant reduction in parasite load in several organs analyzed, without causing toxicity in the animals. The isolated phages or AmpB also induced some reduction in parasitism and Th1-type response in the treated animals, although the response was lower as compared to the combinations between them. In conclusion, the data allows us to infer the possibility of use of combinations between the phage clones and AmpB as immunotherapeutics agents for the treatment against leishmaniasis.