TRANSPLANTATION: Oral Combined Therapy with Probiotics and Alloantigen Induces B Cell?Dependent Long-Lasting Specific Tolerance
J Immunol 2014 192:1928-1937; published ahead of print January 22, 2014, doi:10.4049/jimmunol.1301034
Abstract
Allogeneic hematopietic stem cell transplantation (aHSCT) is widely used for the treatment of hematologic malignancies. Although aHSCT provides a good response against the malignant cells (graft-versus-leukemia [GVL]), it also leads to the development of graft-versus-host disease (GVHD), a severe disease with high mortality and morbidity rates. Therapy for GVHD is commonly based on nonspecific immunosupression of the transplanted recipient, resulting in the concomitant inhibition of the GVL effect. In this study, we propose an alternative approach to specifically suppress GVHD while sparing the GVL, based on oral treatment of transplant donors with recipient Ags, associated with the intake of probiotic Lactococcus lactis as tolerogenic adjuvant (combined therapy). We show that treatment of C57BL/6 donor mice with combined therapy before the transplant protects the recipients F1 (C57BL/6 ? BAL/c) mice from clinical and pathological manifestations of disease, resulting in 100% survival rate. Importantly, the animals keep the immunological competence maintaining the GVL response as well as the response to third-party Ags. The protection is specific, long lasting and dependent on donor IL-10?sufficient B cells activity, which induces regulatory T cells in the host. These data suggest that combined therapy is a promising strategy for prevention of GVHD with preservation of GVL, opening new possibilities to treat human patients subjected to transplantation.
- Ana C. T. Mercadante,
- Suelen M. Perobelli,
- Ana P. G. Alves,
- Triciana Gon?alves-Silva,
- Wallace Mello,
- Ana C. Gomes-Santos,
- Anderson Miyoshi,
- Ana M. C. Faria,
- and Adriana Bonomo
J Immunol 2014 192:1928-1937; published ahead of print January 22, 2014, doi:10.4049/jimmunol.1301034
Abstract
Allogeneic hematopietic stem cell transplantation (aHSCT) is widely used for the treatment of hematologic malignancies. Although aHSCT provides a good response against the malignant cells (graft-versus-leukemia [GVL]), it also leads to the development of graft-versus-host disease (GVHD), a severe disease with high mortality and morbidity rates. Therapy for GVHD is commonly based on nonspecific immunosupression of the transplanted recipient, resulting in the concomitant inhibition of the GVL effect. In this study, we propose an alternative approach to specifically suppress GVHD while sparing the GVL, based on oral treatment of transplant donors with recipient Ags, associated with the intake of probiotic Lactococcus lactis as tolerogenic adjuvant (combined therapy). We show that treatment of C57BL/6 donor mice with combined therapy before the transplant protects the recipients F1 (C57BL/6 ? BAL/c) mice from clinical and pathological manifestations of disease, resulting in 100% survival rate. Importantly, the animals keep the immunological competence maintaining the GVL response as well as the response to third-party Ags. The protection is specific, long lasting and dependent on donor IL-10?sufficient B cells activity, which induces regulatory T cells in the host. These data suggest that combined therapy is a promising strategy for prevention of GVHD with preservation of GVL, opening new possibilities to treat human patients subjected to transplantation.
Administration of probiotics by the oral route also have been shown to modulate the immune response, favoring either pro- (13, 14) or anti-inflammatory (15, 16) responses. Recent studies suggest that TLRs and NF-κB signaling pathways play a crucial role in the outcome of the response (17?21). Also, probiotics can influence the integrity of the gut epithelial cell barrier through modulation of mucus, defensins, and IgA production, reduction of bacterial adhesion, and enhancement of tight junction and cell survival (22?24).