PubMed Health⌕ Search

Biomedical subjects

Michael J Pinkoski

Publications and source records attributed to Michael J Pinkoski.

10 recordsLinked to original sources
PubMed2006

Mitochondria, apoptosis and autoimmunity.

A functional immune system is dependent on the generation and selection of a lymphocyte repertoire that is sufficiently diverse to respond to innumerable foreign antigens yet be adequately self-tolerant to avoid the development of autoimmunity. Programmed cell death by a process known as apoptosis is responsible for negative selection of nonreactive leukocyte precursors and autoreactive thymocytes, killing of infected and transformed cells by cytotoxic lymphocytes and deletion of superfluous activated lymphocytes by activation-induced cell death (AICD) and peripheral deletion at the termination of an immune response. Mitochondrial respiration is required to meet the energy requirements of activated and proliferating peripheral lymphocytes. Several mitochondrial proteins have been implicated as regulators of apoptosis in the immune system that are required for prevention of autoimmunity. Recent discoveries have shed light on mitochondrial functions as they relate to cell death, including caspase-dependent and -independent apoptosis, mitochondrial death substrates and events that disable mitochondrial functions during apoptosis. These discoveries, taken with reports that the specific manner by which a cell dies greatly impacts on the nature of subsequent immune responses, highlight an exciting era of research on mitochondrial function and its role in apoptosis and the effects on immune responses.

Animals↗
PubMed2005

CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.

The 'help' provided by CD4+ T lymphocytes during the priming of CD8+ T lymphocytes confers a key feature of immune memory: the capacity for autonomous secondary expansion following re-encounter with antigen. Once primed in the presence of CD4+ T cells, 'helped' CD8+ T cells acquire the ability to undergo a second round of clonal expansion upon restimulation in the absence of T-cell help. 'Helpless' CD8+ T cells that are primed in the absence of CD4+ T cells, in contrast, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation, but do not undergo a second round of clonal expansion. These disparate responses have features of being 'programmed', that is, guided by signals that are transmitted to naive CD8+ T cells during priming, which encode specific fates for their clonal progeny. Here we explore the instructional programme that governs the secondary response of CD8+ T cells and find that helpless cells undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Regulation of Trail expression can therefore account for the role of CD4+ T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.

Animals↗
PubMed2005

The role of p53 and Fas in a model of acute murine graft-versus-host disease.

Graft-vs-host disease (GVHD) is a devastating, frequently fatal, pathological condition associated with lesions in specific target organs, including the intestine, liver, lung, and skin, as well as pancytopenia and alopecia. Bone marrow (BM) atrophy is observed in acutely diseased animals, but the underlying mechanisms of hemopoietic stem cell depletion remained to be established. We used an experimental mouse model of acute GVHD in which parental cells were injected into F(1) hosts preconditioned by sublethal irradiation. The resulting graft-vs-host response was kinetically consistent, resulting in lethality within 3 wk. We observed disease pathology in the liver and small intestine, and consistent with previous observations, we found BM atrophy to be a factor in the onset of acute disease. The product of the protooncogene, p53, is known to be a key player in many physiological examples of apoptosis. We investigated the role of p53 in the apoptosis of BM cells (BMC) during the development of acute disease and found that at least one copy of the p53 gene is necessary for depletion of BM and subsequent lethality in host animals. BM depletion was preceded by induction of the death receptor, Fas, on the surface of host stem cells, and induction of Fas was coincidental with the sensitization of BMC to Fas-mediated apoptosis. Our data indicate that BM depletion in acute GVHD is mediated by p53-dependent up-regulation of Fas on BMC, which leads to Fas-dependent depletion and subsequent disease.

Acute Disease↗
PubMed2005

Apoptosis in the regulation of immune responses.

Apoptosis, or programmed cell death, is an active process required for the regulation of immune responses. T cell apoptosis may represent a protective mechanism that limits peripheral damage by T cells during immune response. The underlying biological processes responsible for morphological aspects of apoptosis are becoming better defined. Concepts reviewed here include caspase activation, death pathways, and crosstalk between death ligands and their receptors.

Animals↗
PubMed2003

Egr family members regulate nonlymphoid expression of Fas ligand, TRAIL, and tumor necrosis factor during immune responses.

The Fas ligand (FasL)/Fas pathway is crucial for homeostasis of the immune system and peripheral tolerance. Peripheral lymphocyte deletion involves FasL/Fas in at least two ways: coexpression of both Fas and its ligand on T cells, leading to activation-induced cell death, and expression of FasL by nonlymphoid cells, such as intestinal epithelial cells (IEC), that kill Fas-positive T cells. We demonstrate here that superantigen Staphylococcus enterotoxin B (SEB) induced a dramatic upregulation of FasL, TRAIL, and TNF mRNA expression and function in IEC from BALB/c and C57BL/6 mice. Using adoptive transfer in which CD4(+) T cells from OT-2 T-cell receptor transgenic mice were transferred into recipients, we observed an induction in IEC of FasL, TRAIL, and TNF mRNA after administration of antigen. Specific Egr-binding sites have been identified in the 5' promoter region of the FasL gene, and Egr-1, Egr-2, and Egr-3 mRNA in IEC from mice treated with SEB and from transgenic OT-2 mice after administration of antigen was upregulated. Overexpression of Egr-2 and Egr-3 induced endogenous ligand upregulation that was inhibited by overexpression of Egr-specific inhibitor Nab1. These results support a role for Egr family members in nonlymphoid expression of FasL, TRAIL, and TNF.

Adoptive Transfer↗
PubMed2002

Nonlymphoid Fas ligand in peptide-induced peripheral lymphocyte deletion.

Peripheral lymphocyte deletion is required for reduction of lymphocyte numbers after expansion in response to antigen. Peripheral deletion is mediated in part by the activation of apoptosis by engagement of the death receptor, Fas (CD95), by its ligand, Fas ligand (FasL; CD95L), among other mechanisms. Here we used T cell receptor (TCR) transgenic animals to examine the role of inducible expression of nonlymphoid FasL in response to peptide antigen. Antigenic challenge of TCR transgenic mice resulted in increased expression of FasL in a number of nonlymphoid tissues including the epithelium of the small intestine. Similar results were obtained in an adoptive transfer system in which TCR transgenic T cells were transferred into recipient animals. The functional relevance of nonlymphoid FasL in peripheral deletion is supported by the observation that FasL-deficient gld animals showed a significantly reduced rate of clearance of transferred antigen-specific lymphocytes, although the lymphocytes themselves were wild type for FasL. These observations were supported further by studies in a transgenic mouse model where lacZ was expressed under the control of the proximal promoter of the FasL gene. Using these transgenic mice, we observed induced activity of the FasL promoter in intestinal epithelial cells throughout the crypts and villi, where we also observed infiltration of activated T cells. These data demonstrate that nonlymphoid FasL is expressed in response to peripheral T cell activation and participates in the regulation of T cells that infiltrate peripheral tissues.

Adoptive Transfer↗
PubMed2002

Tumor necrosis factor alpha up-regulates non-lymphoid Fas-ligand following superantigen-induced peripheral lymphocyte activation.

Members of the tumor necrosis factor (TNF) and TNF receptor families play important roles in inducing apoptosis and mediating the inflammatory response. Activated T lymphocytes can trigger the expression of Fas-ligand on non-lymphoid tissue, such as intestinal epithelial cells (IEC), and this, in turn, can induce apoptosis in the T cells. Here, we examine the role of TNFalpha in this feedback regulation. Injection of TNFalpha into mice caused a rapid up-regulation of Fas-ligand mRNA in IEC. TNFalpha-induced activation of the Fas-ligand promoter in IEC requires NF-kappaB as this was blocked by an I-kappaBalphaM super-repressor and by mutation of an NF-kappaB site in the Fas-ligand promoter. Activation of T cells by antigen induced Fas-ligand expression in IEC in vivo in wild type, but not in TNFalpha-/- or TNFR1-/- mice. These results define a novel pathway wherein TNFalpha, produced by activated T cells in the intestine, induce Fas-ligand expression in IEC. This is the first observation that one member of the TNF superfamily mediates the regulation of another family member and represents a potential feedback mechanism controlling lymphocyte infiltration and inflammation in the small intestine.

Animals↗
PubMed2002

Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis.

The role of the tumor suppressor p53 as a key regulator of inflammation was examined in murine collagen-induced arthritis (CIA), a model of rheumatoid arthritis. Wild-type DBA/1 mice develop progressive arthritis in this model, in which p53 expression and apoptosis are evident in the synovial cells. In contrast, the joints of p53(-/-) DBA/1 animals with CIA showed increased severity of arthritis using clinical and histological scoring methods with almost no apoptosis. Consistent with this, collagenase-3 expression and cytokine production (interleukin-1 and interleukin-6) in the joints of p53(-/-) mice with CIA were significantly greater than in wild-type mice. Anti-collagen antibody titers, however, were not different. Therefore, p53 expression occurs during inflammation and acts to suppress local inflammatory responses. Because mutations in p53 have been described in the synovial membrane of rheumatoid arthritis patients, the loss of p53 function in synoviocytes or other cells in the joint because of dominant-negative mutations might contribute to invasion and destruction of the joint in this disease.

Animals↗
PubMed2002

Lymphocyte apoptosis: refining the paths to perdition.

Significant advances have been made in the study of mechanisms by which apoptosis regulates immune function. One area receiving renewed attention is killing of target cells by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. A new perspective suggests that granzyme B enters cells via receptor-mediated endocytosis, after which it can act via mitochondrial disruption to trigger apoptotic pathways. The study of intracellular mechanisms driving lymphocyte death also saw major advances as the Bcl-2 family of proteins continues to grow in number and complexity. In addition, the intricacies of the mitochondrial role in apoptosis are starting to unravel with reports of novel proteins, such as Smac/DIABLO, and old proteins, such as heat shock proteins, playing new roles in regulating cell death.

Animals↗