Regulatory activity of endogenous and exogenous transforming growth factor beta in experimental intestinal immunopathology.
Acute graft-versus-host disease (GvHD) is an inflammatory disorder associated with generalised damage to epithelial tissues, including the gastrointestinal tract. There is increasing evidence that this pathology is due to the effects of cytokines on epithelial cell proliferation and differentiation. However, it is unclear whether factors derived from immune cells act directly on epithelial cells or via other mediators whose principal role is to regulate cell growth under normal or diseased conditions. We show here that the increased crypt cell turnover and lymphocytic infiltration which occurs in the jejunum of mice with graft-versus-host reaction (GvHR) is accompanied by decreased enterocyte expression of transforming growth factor beta 2. Administration of exogenous TGF beta inhibits the crypt hyperplasia of GvHR and reduces systemic manifestations of GvHR such as increased splenic natural killer (NK) cell activity. In parallel, neutralisation of endogenous TGF beta by monoclonal antibody exacerbates both the proliferative and inflammatory components of intestinal and systemic GvHR. Thus, the immune system may induce epithelial pathology at least in part by altering the production of endogenous TGF beta. This cytokine may therefore prove a useful focus for therapeutic intervention in immunopathologies such as GvHD.
Mowat
A M
AM
Department of Immunology, University of Glasgow, Western Infirmary, Scotland, UK.
Garside
P
P
Fitton
L A
LA
Higley
H R
HR
Carlino
J A
JA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006086:Graft vs Host Disease / Q000276:immunology*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D007583:Jejunum / Q000166:cytology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000906:Antibodies; D016207:Cytokines; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma