SPLENIC T-HELPER CELL TYPE-1 CYTOKINE PROFILE AND EXTRAMEDULLARY HEMATOPOIESIS IN SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE WITH INFLAMMATORY-BOWEL-DISEASE (IBD)

Scid mice develop a severe, chronic, and lethal IBD 3-6 months after e ngraftment of gut wall from immunocompetent congenic donors, induced b y donor-derived CD4(+) T cells migrating from the graft [7]. We have i nvestigated intracellular T-helper type 1 (Th1) cytokines in the splee ns of gut wall-transplanted scid mice with IBD. Increased fractions of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha ) and IL-2-positive CD4(+) T cells were found in the spleens of diseas ed mice compared with control mice. Moreover, a small but significant population of CD4(+) T cells which stained positive for granulocyte-ma crophage colony-stimulating factor (GM-CSF) was found in scid mice wit h IBD but was virtually absent in congenic non-scid control mice. Clon ing of granulocyte/macrophage colony-forming cells (G/M-CFC) revealed that both non-transplanted scid mice and scid mice with IBD had an 8-1 4-fold increase in splenic G/M-CFC compared with control mice. No sign ificant difference in the number of G/M-CFC per total spleen was found between non-transplanted and disease acid mice, although both groups of mice showed a nearly two-fold increase compared with control mice. G/M-CFC were never found in the thymus, liver or lymph nodes of diseas ed mice. Immunohistochemistry revealed that the multinucleated giant c ells observed in the gut wall of diseased mice did not represent haema topoietic foci, but were derived from macrophages. These observations point towards a dominant role for Th1-type CD4(+) T cells in the immun opathogenesis of IBD, whereas haematopoiesis does not seem to be affec ted by the development of the disease.