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J Steiger

Publications and source records attributed to J Steiger.

At least 37 records · Page 2Linked to original sources
PubMed1996

Prolonged islet allograft acceptance in the absence of interleukin 4 expression.

Murine CTLA4/Fc therapy leads to permanent engraftment of islet allografts in interleukin 4 (IL-4) knockout (IL-4-/- mice. Interestingly, IL-4+/- hosts were more resistant to tolerance induction than IL-4-/- mice. An IL-2/Fc fusion protein abrogates the effect of CTLA4/Fc therapy while an IL-4/Fc fusion protein tends to inhibit rather than enhance the effect of CTLA/Fc treatment in IL-4-/- recipients. We conclude that allograft acceptance requires principally a blockade of T cell activation rather than 'immune deviation' of the T cell activation program to Th2 cytokines (i.e. IL-4).

Animals↗
PubMed1995

Ex vivo coating of islet cell allografts with murine CTLA4/Fc promotes graft tolerance.

To test the hypothesis that blockade of B7-triggered costimulation by donor cells could preclude allograft rejection, we coated crude islet allograft preparations in vitro for 1 h with a murine CTLA4/Fc fusion protein. Murine CTLA4/Fc blocks the proliferative response in primary mixed lymphocyte cultures (MLC) and Con A-stimulated murine spleen cell cultures by 85 to 95%. Responder cells from a primary MLC containing mCTLA4/Fc were hyporesponsive upon restimulation to the same stimulator cells in a secondary MLC lacking mCTLA4/Fc. Because of mutations in the Fc gamma RI and C'1q binding sites of the Fc portion of the murine CTLA4/Fc fusion protein, the molecule binds to, but does not target, cells for Ab-dependent cellular cytotoxicity or complement-directed cytolysis. Although systemic immunosuppression was not applied, 42% (10 of 24) of B6AF1 recipients of islet allografts pretreated with CTLA4/Fc were permanently engrafted. Further, 50% of hosts bearing functioning islet allografts more than 150 days post-transplant were formally proved to be tolerant to donor tissues. A persistent CD4+ and CD8+ T cell infiltrate surrounding, but not invading, islet grafts in tolerant hosts was discerned. In control experiments, 89% (8 of 9) of islet allografts coated with mIgG3, and 100% (n = 10) pretreated with media alone were rejected. Thus, we conclude that 1) B7-triggered costimulation by donor APCs is an important element of rejection, and 2) blockade of the B7 pathway by in vitro allograft manipulation is able to induce tolerance.

Abatacept↗
PubMed1995

IL-2 knockout recipient mice reject islet cell allografts.

The IL-2 pathway is portrayed often as central to allograft rejection. To test this hypothesis, we studied IL-2-deficient mice as allograft recipients. IL-2 gene knockout (KO) mice reject islet allografts and demonstrate a classical mononuclear leukocytic infiltrate, containing CD4+ and CD8+ T cells, surrounding and invading the islet allografts. Moreover, allograft rejection in the IL-2 KO mouse is associated with intragraft expression of certain cytokine and CTL attack molecule genes (e.g. IFN-gamma, IL-4, IL-7, IL-10, and granzyme B). In separate experiments, IL-2 KO mice generated CTLs in response to in vivo challenge with allogeneic tumor cells. Although IL-2 KO mice reject allografts in vivo, spleen cells from immunologically naive IL-2 KO mice exhibit a diminished proliferative response to mitogens in vitro that could be restored largely by exogenous IL-2, IL-4, or IL-7. The paradoxical ability to execute graft rejection in vivo despite near absent T cell proliferative responses in vitro may result from the expression of IL-7 in vivo, but not in vitro. Con A-stimulated bulk spleen cell cultures derived from IL-2 KO mice were essentially devoid not only of IL-2 but also IL-7 gene transcripts. These data indicate that 1) IL-2 is not the sole T cell growth factor capable of supporting allograft rejection and 2) expression of IL-4, but not IL-2, during the allograft response does not lead inevitably to tolerance.

Animals↗
PubMed1995

Administration of noncytolytic IL-10/Fc in murine models of lipopolysaccharide-induced septic shock and allogeneic islet transplantation.

Numerous studies have suggested the potential application of IL-10 as an anti-inflammatory and as an antirejection agent. Unfortunately, cytokines have short circulating t1/2 We developed a murine IL-10/Fc gamma 2a immunoligand that possesses the biologic functions of IL-10 and the long circulating t1/2 in vivo, characteristic of Igs. We mutated the Fc gamma 2a fragment to render the immunoligand ineffective in directing Ab-dependent cell-mediated cytotoxicity and complement-directed cytolysis (noncytolytic IL-10/Fc (IL-10/Fc2-)). In terms of IL-10 activity, IL-10/Fc2- was as effective as rIL-10 mole per mole in preventing lethal septic shock, but the immunoligand had a prolonged period of efficacy in accord with its extended circulating half-life. Contrary to expectations, IL-10/Fc2- treatment tended to accelerate the destruction of islet cell allografts and increase the levels of granzyme B gene expression in local draining lymph nodes. These data suggest that the enhanced cytotoxic activity of allograft-destroying CTLs may contribute to the accelerated allograft rejection. Finally, our studies suggest that a noncytolytic IL-10/Fc fusion protein provides a useful tool to study the biologic effects of IL-10 in vivo and may provide a useful agent for the prevention and treatment of septic shock.

Animals↗
PubMed1994

Cytokines and the Th1/Th2 paradigm in transplantation.

With studies elucidating the cytokine programs associated with T-cell activation, allograft rejection and tolerance induction, the Th1/Th2 paradigm has become a unifying model to explain the observed cytokine profiles. The proof that these cytokines mediate allograft tolerance, however, is at best indirect. More recent studies highlighting the redundant and pleiotropic nature of cytokine networks suggest that the Th1/Th2 paradigm may not be sufficient to explain fully the mechanisms underlying allograft tolerance.

Animals↗
PubMed1987

Platelet activating factor (PAF) is a potent stimulator of porcine tracheal fluid secretion in vitro.

Mucus hypersecretion is a major clinical feature of chronic obstructive lung diseases such as asthma. The possible role of the inflammatory and bronchoconstrictor ether lipid PAF (platelet activating factor) has been studied in isolated porcine trachea with the tantalum 'hillock' technique used to visualize fluid production from tracheal submucosal glands. PAF caused a rapid, dose-dependent (0.001-1 nM) stimulation of fluid secretion which could be detected after 5 min and which increased with time up to at least 15 min. The PAF-induced fluid secretion was unaffected by both antagonists of histamine, acetylcholine and leukotriene D4 and inhibitors of prostaglandin and leukotrienes synthesis. A purported PAF receptor antagonist (CV 3988) inhibited the PAF responses in a dose-dependent manner implying a receptor-mediated event. These results may be of relevance to the mucus hypersecretion seen in chronic airway diseases.

Animals↗