After intravenous injection of 10(5) purified, lymph node (LN)-derived dm2 (H-2d/Ld-) CD4+ T cells into young C.B-17 scid/scid (severe combined immunodeficiency, SCID) mice (H-2d/Ld+), the transplanted Ld-T cells show a selective pattern of engraftment: they repopulate the spleen, the lamina propria of the small intestine and the mesenteric LN (but not other peripheral LN) of the immunodeficient host. CD4+ cells repopulating different lymphoid organs of the SCID recipient mice produce interleukin-2 (IL-2) and interleukin-4 (IL-4) in response to polyclonal stimulation in vitro. Some evidence has recently been provided that cytokines (e.g. IL-4) present at the site of antigen stimulation in vivo decisively influence the pattern of cytokines expressed by T cells activated at these sites. We therefore asked if neutralization of IL-4 by chronic treatment of SCID mice with high doses of recombinant soluble IL-4 receptor (sIL-4R) changes the IL-4 or IL-2 expression pattern of CD4+ T cells adoptively transferred into young SCID recipients. Transplanted SCID mice were chronically treated with two different, recombinant murine sIL-4R proteins. The experimental series further included groups of transplanted SCID mice treated with a recombinant human sIL-4R protein (which does not bind murine IL-4), treated with the anti-murine IL-4 monoclonal antibody (MoAb) 11B11, or non-treated. Transplanted SCID mice treated with the recombinant murine sIL-4R protein preparations displayed detectable sIL-4R serum levels, which demonstrates that the substitution therapy could maintain neutralizing serum levels of anti-IL-4 activity in SCID mice. By contrast, no serum sIL-4R levels were detectable in the sensitive ELISA readout in transplanted SCID mice which were non-treated, treated with the MoAb 11B11, or treated with the recombinant humans sIL-4R protein. The efficiency and the pattern of CD4+ T-cell engraftment, and the lymphokine-producing phenotype of the engrafted dm2 CD4+ cells, was not affected by the continuous IL-4-neutralizing treatment of mice with either the MoAb 11B11 or the soluble IL-4R preparations. Hence, in contrast to the published evidence of the dramatic effect of IL-4 on the lymphokine-producing phenotype of CD4+ T cells stimulated in vitro or in vivo, the chronic suppression in vivo of IL-4 activity (by either different sIL4-R protein constructs, or by the anti-IL-4 MoAb 11B11) did not lead to preferential engraftment of Th1-type CD4+ T cells after adoptive transfer of CD4+ T-cell populations into an immunodeficient recipient.

No abstract

Crohn's disease and Ulcerative Colitis, collectively termed inflammatory bowel disease (IBD), are chronic inflammatory disorders of the bowel. It is generally accepted that the pathology associated with IBD is characterized by a hyper-reactive immune response in the gut wall directed against the commensal intestinal bacterial flora, and that the CD4+ T cells dominate the adaptive immune response. Chemokines are small proteins involved in the guidance of migration of immune cells during normal homeostasis and inflammation. Chemokines have been shown to play a central role in recruiting inflammatory cells to the inflamed bowel of IBD patients, making the chemokine/receptor system appealing as new therapeutic targets to sustain remission in these patients. In the severe combined immunodeficiency transfer model of colitis, which histopathologically resembles human IBD, low numbers of CD4+CD25- T cells from congenic normal mice are transplanted into immune deficient mice, which in turn develop a chronic lethal colitis within 1-2 months. By simultaneous transplantation of CD4+CD25+ regulatory T cells (Tregs) it is possible to hinder development of colitis. Thus the model is well suited for studying mechanisms underling both the effector and the regulatory components of chronic inflammation. In the current review we discuss new possible targets for immune therapy in colitis.

The present work shows that addition of mouse beta interferon (IFN) to murine bone marrow cells cultured in the presence of pokeweed mitogen-spleen-CM results in an increase in the proportion and number of diffuse colonies. Addition of IFN early in the culture period inhibits the development of the cytotoxic capacity typical for normal diffuse colonies. Addition of IFN late in the culture period, when diffuse colonies have already been formed, enhances the cytotoxic activity of individual colonies. The cellular composition of diffuse colonies was nearly identical in non-cytotoxic and strongly cytotoxic colonies. It is concluded that IFN profoundly affects development and function of cytotoxic diffuse colonies.

Twelve human T-cell lines were derived from cultures stimulated with phytohaemagglutinin (PHA) or with the recall antigen purified protein derivative (PPD), using the one-step agar colony method, followed by further expansion of individual T-cell colonies for at least 50 days. As judged by monoclonal antibodies, two of the PHA-derived T-cell lines carried the helper-inducer (H-I) phenotype and two the suppressor-cytotoxic (S-C) phenotype. Four PPD-derived cell lines displayed the H-I phenotype, and three of these proliferated specifically when challenged with the recall antigen, whereas the fourth did not. Four PPD-induced T-cell lines carried the S-C phenotype, and only one of these was antigen-specific. All cell lines with H-I phenotype displayed helper cell activity as determined by Ig secretion of B lymphocytes stimulated with a T-cell-dependent polyclonal B-cell activator. Cell lines with the S-C phenotype had no such helper activity and suppressed Ig responses in the presence of freshly isolated T cells. Thus, a good correlation between phenotypic markers and functions was found. T helper cells and T suppressor cells can be differentiated by means of both polyclonal and antigenic stimuli.