Lithothamnion muelleri regula a resposta inflamatória, lesão de órgãos alvo e letalidade na doença do enxerto-versus-hospedeiro

Abstract

Graft-versushost disease (GVHD) is the greatest complication limiting the clinical utility of allogeneic hematopoietic stem cell transplantation (HSCT), in which lymphocytes of donors (graft) are activated in response to host antigen. An inflammatory cascade involving cytokine/chemokine production resulting in enhanced expression of major histocompatibilitycomplex (MHC) and costimulatory molecules on tissue ntigen-presenting cells (APCs) isalso involved in the GVHD pathogenesis. Subsequently to the transplant donor T cells become activated through recognition of host alloantigens and differentiate into effector T cells that migrate to target organs, recruit other leukocytes and lead to local and systemicinflammation. Lithothamnion muelleri (LM) is a marine red algae with anti-inflammatory properties. Moreover, mineral-rich extracts obtained from LM have been shown to reduce the inflammation associated to gastrointestinal polyps and studies revealed that polysaccharidesfrom alga from same class as the LM have arrtiinflammatory properties, antitumor and immunomodulatory activity. The present study evaluated the effects of treatment with the algae Lithothamnion muelleri in the pathogenesis of acute graft-versushost disease (GVHD), using a model of adoptive transfer of splenocytes from WT to B6D2Fl mice. The engraftment process may also cause a graft versus tumor response which is useful for controlling residual malignant diseases, eliminating tumor cells. Therefore, therapies that reduce GVHD without interfering in GVT are important. Mice treated with LM showed reduced mortality andclinical signs of disease when compared to untreated mice. These findings were associated with lower target organ damage, decreased production of pro-inflammatory cytokines and chemokines (CCL-3, IFN-y, TNF-oi, CCL-2 and CCL-5), reduction of leucocyte recruitment and lower bacterial translocation into the intestine, liver and blood. Moreover, animals treated with LM showed no change in plasma creatinine levels (suggesting preservation of renal function) and decreased levels of IFN-y and CCL2 in brain. We also observed that the treatment with LM did not alter the beneficial effect of graft-versus-tumor. In conclusion, LM appears as a new candidate with potential therapeutic application in the treatment of GVHD.