Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3613-3619
Induction of oral tolerance in splenocyte recipients toward
pretransplant antigens ameliorates chronic graft versus host disease in
a murine model
Yaron Ilan,
Israel Gotsman,
Mark Pines,
Roy Beinart,
Michael Zeira,
Meir Ohana,
Elazar Rabbani,
Dean Engelhardt, and
Arnon Nagler
From the Liver Unit, Department of Medicine, and Department of Bone
Marrow Transplantation, Hadassah University Hospital, Jerusalem,
Israel; Institute of Animal Science, Agricultural Research
Organization, The Volcani Center, Beit Dagan, Israel; and ENZO Biochem
Inc, New York, NY.
Chronic graft versus host disease (cGVHD) is a major complication
that can develop after bone marrow transplantation. It involves an
immune-mediated attack by transplanted donor lymphocytes, and often
results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been
recently shown to prevent the development of cGVHD in a murine model.
The aim of this study was to evaluate whether tolerance induction in
bone marrow transplant (BMT) recipients after transplantation, toward
their pretransplant antigens, can alleviate preexisting cGVHD in a
mouse model. cGVHD was generated by infusing 2.5 × 107
splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy)
BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral
tolerance was induced by feeding recipient BALB/c mice with proteins
extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte
transplantation. Tolerance induction was evidenced by a significant
reduction in mixed lymphocyte response of effector splenocytes from
tolerant BALB/c mice transplanted with B10.D2 splenocytes
against BALB/c target splenocytes. Oral tolerance decreased skin
collagen deposits. Reduction of collagen 
1(I) gene expression and
skin collagen were shown by in situ hybridization and histochemistry,
respectively. Liver and bowel biopsy specimens revealed less
inflammation. Serum IL-10 levels were higher in tolerant mice than in
controls, whereas IFN
was significantly reduced. Oral tolerance of
BMT recipients toward their pretransplant antigens after splenocyte
transplantation down-regulated the immune attack by transplanted cells,
thus ameliorating cGVHD.
