TY - JOUR
T1 - Induction of oral tolerance in bone marrow transplantation recipients suppresses graft-versus-host disease in a semiallogeneic mouse model
AU - Nagler, A.
AU - Ohana, M.
AU - Alper, R.
AU - Doviner, V.
AU - Sherman, Y.
AU - Rabbani, E.
AU - Engelhardt, D.
AU - Ilan, Y.
N1 - Funding Information:
This work was supported in part by the following grants: The Roaman-Epstein Liver Research Foundation; Israel Cancer Research Fund; Israel Cancer Association Research Grant. A grant from ENZO Biochem.
PY - 2003/8
Y1 - 2003/8
N2 - Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 × 107 splenocytes from C57BL/6 donor mice into (C57BL/6 × Balb/c)F1 recipient mice, which received 7 Gy 60Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 μg/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system.
AB - Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 × 107 splenocytes from C57BL/6 donor mice into (C57BL/6 × Balb/c)F1 recipient mice, which received 7 Gy 60Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 μg/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system.
KW - GVHD
KW - Immune tolerance
KW - Oral tolerance
UR - http://www.scopus.com/inward/record.url?scp=0042889178&partnerID=8YFLogxK
U2 - 10.1038/sj.bmt.1704145
DO - 10.1038/sj.bmt.1704145
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C2 - 12900772
AN - SCOPUS:0042889178
SN - 0268-3369
VL - 32
SP - 363
EP - 369
JO - Bone Marrow Transplantation
JF - Bone Marrow Transplantation
IS - 4
ER -