Oral combined therapy with probiotics and alloantigen induces B cell-dependent long-lasting specific tolerance.
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.
Department of Experimental Medicine, Brazilian National Cancer Institute, Rio de Janeiro 20231-050, Brazil;
Ana C T
AC
Mercadante
Suelen M
SM
Perobelli
Ana P G
AP
Alves
Triciana
T
Gonçalves-Silva
Wallace
W
Mello
Ana C
AC
Gomes-Santos
Anderson
A
Miyoshi
Vasco
V
Azevedo
Ana M C
AM
Faria
Adriana
A
Bonomo
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007519:Isoantigens / Q000627:therapeutic use*; D013294:Lactococcus lactis / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019936:Probiotics / Q000627:therapeutic use*; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D007519:Isoantigens; D016753:Interleukin-10