Biomedical subjects

Richard N Mitchell

Publications and source records attributed to Richard N Mitchell.

24 records · Page 2Linked to original sources

PubMed2002

Cold ischemia induces isograft arteriopathy, but does not augment allograft arteriopathy in non-immunosuppressed hosts.

Prolonged cold ischemia has been suggested as a factor that will exacerbate later graft arterial disease (GAD), a major limiting factor for long-term transplant survival. We therefore examined the effects of cold ischemia on GAD as well as adhesion molecule and cytokine expression in murine cardiac grafts. Mild GAD developed in isografts undergoing 4-hour cold ischemia. Relative to control isografts, cold ischemia induced transiently enhanced endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at 4 hours post-transplant. There was also transiently-augmented gene expression of interleukin (IL)-1beta, IL-6, and transforming growth factor-beta in these cold-ischemic isografts. By 3 days post-transplantation, however, there were no longer any differences between control and cold ischemic isografts. Cold ischemia did not significantly affect the final grade of either parenchymal rejection or GAD in long-term (4 to 12 weeks) major histocompatibility complex (MHC) I- or MHC II-mismatched allografts molecules transplanted without immunosuppression. At early time points after cold ischemia (4 to 24 hours), allografts mismatched for MHC I and/or MHC II showed enhanced expression of ICAM-1 and cytokines comparable to that seen in isografts. By day 7 post-transplant, both control and cold ischemia allografts showed comparable expression of cytokines and adhesion molecules. Although prolonged cold ischemia can initiate mild GAD in isografts by transiently enhancing antigen non-specific inflammatory responses, it does not significantly augment subsequent alloresponses.

Animals↗

PubMed2002

Antigen binding to GM1 ganglioside results in delayed presentation: minimal effects of GM1 on presentation of antigens internalized via other pathways.

Plasma membrane rafts are sphingolipid- and cholesterol-rich patches that function as membrane trafficking and surface signalling regions. Ganglioside GM1 is an integral component of these microdomains, and Escherichia coli enterotoxin B subunit (EtxB) is a pentamer that binds with high affinity to GM1 resulting in GM1 cross-linking. We previously demonstrated that antigen coupled directly to EtxB resulted in enhanced presentation relative to antigen taken up by fluid-phase endocytosis. Here we demonstrate a new role for GM1 in antigen presentation by examining the effects of cross-linking GM1 on the kinetics of presentation and processing of antigen by the B-cell receptor (BCR), fluid-phase endocytosis and GM1-targeted antigen. EtxB bound to B cells does not augment the subsequent kinetics or magnitude of presentation of either BCR-internalized antigen or soluble antigen. Moreover, presentation of GM1-bound antigen is significantly slower than antigen presentation following BCR-mediated uptake. In contrast to the rapid internalization of BCR-bound antigen (which has a half life of 60 min), the majority of EtxB-bound antigen forms a plasma membrane depot detectable for many hours after initial incubation (and with a half life of 12 hr). We conclude that cross-linking of GM1 by EtxB minimally affects the processing and presentation of antigens internalized via other pathways. Nevertheless, binding of antigens to GM1 results in delayed presentation that has important implications for in vivo immunization using GM1-targeted adjuvants.

Animals↗

PubMed2002

Interferon gamma modulates trauma-induced muscle wasting and immune dysfunction.

OBJECTIVE: To test the effect of burn injury in mice congenitally deficient in interferon gamma (IFN-gamma) and as well as in wild-type animals treated with IFN-gamma neutralizing antibody. SUMMARY BACKGROUND DATA: The mechanisms underlying muscle wasting following burn trauma are incompletely characterized, although the hypercatabolic state is a consequence of increased proteasomal degradation. Concurrently, burn injury results in an immunocompromised state, and subsequent infections are the leading cause of morbidity and mortality in these patients. IFN-gamma, best conceptualized as a macrophage activating protein, modulates a variety of biologic pathways potentially relevant to muscle wasting and immune dysfunction. METHODS: Mice received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Protein synthesis and degradation rates were measured. Lymphocyte subpopulation expression of major histocompatibility complex I (MHC I) molecules was assessed by flow cytometry, and proliferation capacity was measured using mixed lymphocyte reaction. RESULTS: IFN-gamma is critically involved in burn-induced weight loss; moreover, absence of IFN-gamma virtually abolished skeletal muscle hypercatabolism following burn injury. Lymphocyte proliferation and MHC I expression in the setting of burn trauma are also normalized in the absence of IFN-gamma. Both antigen presentation and proliferation functions are independently affected. CONCLUSIONS: IFN-gamma plays a fundamental role in mediating the hypercatabolic state of multiple cell types following burn trauma.

Animals↗

PubMedDate not supplied

The role of stem cells in the response to myocardial and vascular wall injury.

Myocardium has long been considered a terminally differentiated tissue, with injury invariably leading to replacement with fibrosis. However, new reports suggest potential roles for circulating or endogenous stem cells in repopulating myocardium after irreversible injury. Unfortunately, these benefits may represent a double-edged sword. While offering exciting possibilities for therapy following myocardial infarction (MI), stem cells are also increasingly implicated in contributing to a number of vascular pathologies, including the formation of graft arterial disease (GAD) after cardiac transplantation. In this review, the function of stem cells in repopulating infarcted myocardium and their role in the pathogenesis of intimal hyperplastic lesions such as GAD will be discussed.

Animals↗

PubMedDate not supplied

CD8 T cells are sufficient to mediate allorecognition and allograft rejection.

Different T cell subsets may play different roles in allorecognition and allograft rejection. It has been suggested that CD8 T cells can only initiate rejection with help from CD4 T cells. Since CD8 T cells may have different requirements for allorecognition and for costimulation, it is important to clarify the role of CD8 cells in rejection. We examined the role of CD8 cells in allorecognition using a TCR transgenic mouse transplantation model. In our study, CD8 cells were able to recognize alloantigens and reject allografts in the absence of help from CD4 T cells. Furthermore our study provides a model to study the mechanisms of CD8-mediated allograft rejection. It may be important in the future, to consider that CD8 T cells may need to be targeted independently of CD4 T cells in strategies used to prevent rejection and induce tolerance.

Animals↗

PubMedDate not supplied

Allograft arteriopathy: pathogenesis update.

Allograft arteriopathy is a vascular intimal proliferative process that occurs in all solid organ transplants and stands as the single most significant obstacle to successful long-term solid organ transplantation; it shares a number of pathologic features with restenosis lesions and atherosclerosis. This article will review some of the newer developments in our understanding of the immunological and vascular biology underpinnings of the disease, including the roles played by cytokine and chemokine mediators in recruiting and activating both inflammatory cells, as well as smooth muscle cell precursors.

Arteriosclerosis↗