Antagonizing leukotriene B4 receptors delays cardiac allograft rejection in mice.

Background: Allograft rejection is a cellular immunological/inflammatory response that is, in part, directed by potent proinflammatory mediators. This study was designed to test the hypothesis that leukotriene B4 (LTB4) may have a role in graft rejection and that LTB4 receptor antagonists may be clinically useful in the treatment of allograft rejection.

Methods: We evaluated the potent and selective LTB4 receptor antagonist CP-105696 in a murine heterotopic cardiac allograft model with oral dosing daily for 28 days or in an induction protocol (day -1 to day 3).

Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation.

Here, we have studied the activity of a novel protein-tyrosine kinase inhibitor that is selective for the Src family of tyrosine kinases. We have focused our study on the effects of this compound on T cell receptor-induced T cell activation, a process dependent on the activity of the Src kinases Lck and FynT. This compound is a nanomolar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells, demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleukin-2 (IL-2)-induced T cell proliferation.

Identification of T cell subsets and class I and class II antigen expression in islet grafts and pancreatic islets of diabetic BioBreeding/Worcester rats.

The BioBreeding/Worcester (BB/Wor) rat develops a spontaneous disorder that closely resembles human insulin-dependent (Type I) diabetes mellitus. The syndrome is preceded by lymphocytic insulitis that destroys pancreatic beta cells. The morphologic features of the spontaneous insulitis lesions are also observed within islets transplanted beneath the renal capsule of diabetes-prone and diabetic animals.

Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells.

Diabetes-prone BioBreeding/Worcester (BB/Wor) rats received thrice weekly injections of mAb against antigens expressed on the surface of all T cells (OX19), cytotoxic/suppressor, and NK cells (OX8), helper/inducer cells (W3/25, OX35, OX38), and Ia+ cells (OX6, 3JP, OX17). Treatment with OX8 or OX19 achieved stable reductions of splenic and peripheral blood NK cells and helper/inducer T lymphocytes, respectively, and protected against diabetes. OX19 injections also prevented lymphocytic insulitis, thyroiditis, and the synthesis of autoantibodies to thyroid colloid and smooth muscle antigens.