Oral Combined Therapy with Probiotics and Alloantigen Induces B Cell–Dependent Long-Lasting Specific Tolerance

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.

Neutrophils Plasticity: The Regulatory Interface in Various Pathological Conditions

“…In this way, when Treg cells are depleted early after the transplantation, the GVHD protection is abolished, showing Treg induction within the host right after transplantation. These specific suppressor effects are compatible with the antigen-specific suppression previously observed with Treg cells [97,98]. (Figure 3).…”

Fecal microbiota transplant after hematopoietic SCT: report of a successful case

“…A recent study showed that probiotics played an important role in B-celldependent specific tolerance, in an animal model. 5 Clearly, there is much more to explore and learn about the intestinal microbiota, and their implications for human health.…”

Influence of the Gut Microbiome on Autoimmunity in the Central Nervous System

“…Probiotics also have an effect on B regs . Mercadante et al (102) have shown that L. lactis can promote the generation of IL-10-producing B cells that mediate tolerance in a model of graft-versus-host disease. Clostridium butyricum, when given in combination with specific immunotherapy, significantly increases the frequency of IL-10 + B cells in both mice and humans (103,104).…”