Interferon-gamma is not involved in the intestinal manifestations of the acute murine semiallogenic graft-versus-host disease.
BACKGROUND
The acute murine semiallogenic graft-versus-host disease (GvHD) is known to be associated with Th1 cytokines secreting lymphocytes in the spleen and lymph nodes. However, whether this cytokine secretion pattern is also involved in the intestinal manifestations of acute GvHD (crypt hyperplasia and villous atrophy) is not known, so far.


METHODS
We first investigated the secretion of interleukin (IL) 4 (indicative of Th2-type differentiation) and interferon (IFN) 7 (Th1-type differentiation) by splenic and by small bowel lamina propria lymphocytes. In addition, animals were treated with neutralizing antibodies to IL-4 or IL-12. The effect of this treatment on the intestinal morphology was examined. Second, we also investigated the effect of donor-derived IFN-gamma by using donor lymphocytes from IFN-gamma knock-out animals. Third, animals were treated with the fusion protein OX40-Ig which interferes with the OX40-OX40L interaction and thereby inhibits the intestinal manifestations of acute GvHD.


RESULTS
We found that, whereas splenic lymphocytes secrete an excess of IFN-gamma, lymphocytes of the intestinal lamina propria secrete less IFN-gamma and IL-4 than control animals. When OX40-Ig is administered to animals with acute GvHD, the intestinal histology normalizes as well as the secretion of IFN-y and IL-4, indicating that the intestinal morphology is not affected by the secretion of IFN-gamma by lamina propria lymphocytes. The treatment of animals suffering from acute GvHD with anti-IL-4 and anti-IL-12, which blocks the differentiation of IFN-gamma secreting T-lymphocytes, did not significantly affect the development of crypt hyperplasia or villous atrophy. Furthermore, donor lymphocytes of IFN-gamma knock-out animals also induced the intestinal manifestations of acute GvHD.


CONCLUSIONS
These findings indicate that IFN-gamma is not crucial for the development of crypt hyperplasia and villous atrophy in the murine semiallogenic GvHD.
Stüber
E
E
I. Medizinische Universitätsklinik, Kiel, Germany. estueber@1med.uni-kiel.de
Schlenger
P
P
Von Freier
A
A
Arendt
T
T
Fölsch
U R
UR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000628:therapy*; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007421:Intestine, Small / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D016207:Cytokines; C406562:OX40Ig; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma