Biomedical subjects

J H Russell

Publications and source records attributed to J H Russell.

At least 19 recordsLinked to original sources

PubMed2001

Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias.

Fas-mediated signaling is important for lymphocyte elimination. We investigated lymphocytes for Fas-signaling defects in 20 pediatric patients with chronic hematologic autoimmunity. In 5 of 20 (25%), there was profound resistance to exogenous FasL-mediated lysis, Fas mAb, and anti-CD3. FasL function, though variable, was not significantly different from that of simultaneously evaluated controls. Only 1 patient had a Fas mutation and manifestations of autoimmune lymphoproliferative syndrome. In contrast, lymphocytes from his clinically normal mother with the same mutation were normally sensitive to FasL. In 3 patients, normal Fas-mediated lysis was restored with rhIL-2. IL-2 had no effect in the other 2 patients. Activation and proliferation functions of IL-2 were normal in all 5. We conclude that altered Fas signaling, independent of Fas mutations, can precipitate hematologic autoimmunity. IL-2 can rescue some lymphocytes from this defect. In IL-2 refractory cases, a persistently defective response to IL-2 continues to confer a lymphocyte survival advantage. Hence, altered Fas pathway signaling with or without defective IL-2 responses should be considered in the etiology of hematologic autoimmunity.

Adolescent↗

PubMed2001

Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase.

Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption. Emk(-/-) mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4(+)T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. As Emk(-/-) animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.

Animals↗

PubMed2000

Genetic control of pathogenic mechanisms in autoimmune demyelinating disease.

Multiple sclerosis is a disease of discrete phenotypes in different individuals. Animal models have been useful in identifying self-antigens that become the focus of autoimmune attack and genetic loci that control susceptibility to disease. We have previously demonstrated a role for Fas-dependent pathogenesis in the induction of EAE in B10.PL mice immunized with MBP. Others have indicated a Fas-independent mechanism predominates in SJL mice immunized with PLP. Here we compare the response of (B10.PLxSJL)F1 and parental mice under similar conditions for induction of EAE. The results indicate that immunodominance and dominant pathogenic mechanisms are both under genetic control, but can be inherited independently. The data also indicate that the dominant pathogenic mechanism can change during the course of disease in an individual. Elucidation of the genetic elements controlling pathogenesis during the course of disease would provide important information in designing therapeutic strategies for individuals in a heterogeneous patient population.

Animals↗

PubMed2000

IL-12 enhances IL-2 function by inducing CD25 expression through a p38 mitogen-activated protein kinase pathway.

We previously showed that an IL-2 mutant, Q126D, could induce T cells to proliferate to the same extent as wild-type IL-2 but was unable to sensitize T cells to activation-induced cell death (AICD). Here we show that the partial signaling of Q126D is attributable to its inability to up-regulate the IL-2 receptor alpha chain (CD25). IL-12, which can up-regulate CD25 expression, enhances the ability of Q126D to induce AICD sensitivity and proliferation. IL-12 synergism with Q126D is dependent on CD25 up-regulation because the synergism is absent in CD25-deficient T cells. Inhibition of IL-12-induced up-regulation of CD25 by a p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580, also ablates the synergism between IL-12 and Q126D. Although CD25 is important for IL-2-induced proliferation and AICD sensitivity, it is not absolutely required because a high concentration of IL-2 can overcome the requirement for CD25. Under physiological concentrations of IL-2, CD25 expression is critical for the function of IL-2. IL-12 can enhance the function of IL-2 by up-regulating CD25 in a p38 MAP kinase-dependent manner.

Animals↗

PubMed2000

The role of fas ligand in vivo as a cause and regulator of pathogenesis.

Recent studies have significantly advanced our understanding of the physiological and pathogenic functions of Fas and Fas ligand (FasL) in vivo. In particular, roles for Fas-FasL interactions both in the induction and regulation of organ-specific autoimmune diseases have been defined and in some cases the specific targets and effectors of these interactions have been identified. Understanding the dynamic role of the Fas-FasL pathway in autoimmunity will provide insight into how best to modulate this interaction to achieve therapeutic benefits.

Autoimmune Diseases↗

PubMed1999

Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis.

We have previously demonstrated a role for Fas and Fas ligand (FasL) in the pathogenesis of experimental allergic encephalomyelitis (EAE). However, using an active induction paradigm we could not distinguish between FasL expressed on activated CD4(+) T cells from that expressed on other inflammatory or resident central nervous system (CNS) cells. To address this issue, we have conducted reciprocal adoptive transfer experiments of nontransgenic or myelin basic protein-specific T cell receptor transgenic wild-type, lpr, or gld lymphocytes into congenic wild-type, lpr, and gld hosts. We found that FasL expressed on donor cells is important for the development of EAE, as FasL-deficient lymphocytes transfer attenuated disease. Furthermore, Fas expressed in the recipient animals is important for the progression of EAE, as clinical signs of disease in lpr recipients were dramatically attenuated after transfer of either wild-type or lpr T cells. Surprisingly, these experiments also identified CNS cells as a source of functional FasL. Host-derived FasL appears to be especially important in the recovery from EAE, as many gld recipients of wild-type lymphocytes develop prolonged clinical signs of disease. Thus it appears that FasL plays distinct roles in EAE during the initiation of and recovery from disease.

Animals↗

PubMed1999

The role of the antigen-presenting cell in Fas-mediated direct and bystander killing: potential in vivo function of Fas in experimental allergic encephalomyelitis.

Costimulatory molecules are critical in mediating Fas-dependent direct and bystander lysis. In direct lysis, the APC is the Fas-positive target. It presents Ag to the T cell, thereby activating the T cell. The activated T cell then up-regulates FasL, allowing it to kill the APC. In bystander lysis, the APC again induces FasL expression on the T cell, but the target is a third Fas-positive cell that may lack the appropriate MHC-restricting element to activate the T cell. This study shows that ICAM-1 and B7-1 can serve as important adhesion molecules in direct killing using CD4+ T cell effectors. In bystander killing, B7-1 appears to act as a signaling molecule as well. It has been demonstrated that lpr and gld mice are less susceptible to experimental allergic encephalomyelitis than their wild-type counterparts. In this study, we show that although microglia are poor targets of direct killing, they are capable of stimulating myelin basic protein-specific T cells to kill innocent Fas-positive targets. This presents a possible mechanism for the pathogenesis of experimental allergic encephalomyelitis.

Animals↗

PubMed1999

Role of Fas--FasL interactions in the pathogenesis and regulation of autoimmune demyelinating disease.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) represent complex processes that lead to destruction of oligodendrocytes (ODCs) and myelin. T cells are integral to the development of these diseases, but whether T cell-mediated cytolytic mechanisms are involved in the destruction of MHC Class II-negative targets, such as oligodendroglia and myelin, in the CNS is unclear. The primary lytic mechanism employed by CD4+ T cells is Fas-dependent, but can be MHC-unrestricted. Thus, T cell-mediated Fas-FasL interactions could directly contribute to the pathology of EAE and MS. This review summarizes studies from our laboratory and others that implicate Fas-FasL interactions in both the pathogenesis and regulation of demyelinating diseases.

Animals↗

PubMed1998

Maternal-fetal tolerance is maintained despite transgene-driven trophoblast expression of MHC class I, and defects in Fas and its ligand.

During mammalian pregnancy, one or more semiallogeneic fetuses gestate in direct contact with the maternal circulation and uterine tissue. However, a damaging maternal immune response is not normally provoked. We studied two possible mechanisms for this maternal-fetal tolerance, alone and in combination. First, we directly tested the hypothesis that the striking absence of MHC class I molecules on most placenta trophoblasts protects the fetus from maternal immune attack, by creating transgenic mice which express Ld in giant cell trophoblasts. Second, because Fas ligand (FasL) may contribute to immune privilege, we tested whether functional FasL expression by the fetus, or Fas expression by the mother, contributes to successful reproduction in a fully allogeneic breeding. Our data indicate that neither abnormal expression of MHC class I in giant cells, nor disruption of the Fas-FasL system, nor a combination of these two defects, has an adverse effect on pregnancy outcome. These results suggest that during healthy allogeneic pregnancy, down-regulation of MHC class I and expression of FasL on placenta are not critical events, and other factors must prevent a harmful maternal immune response.

Adoptive Transfer↗

PubMed1997

Partial signaling by cytokines: cytokine regulation of cell cycle and Fas-dependent, activation-induced death in CD4+ subsets.

Fas-dependent, activation-induced death (AID) of T cells has been implicated in the regulation of peripheral T cell populations. We have previously reported that IL-2 plays a unique role in regulating sensitivity to AID in primary CD4+ cells. In this report we have compared the capacity of IL-2, IL-4, and IL-7 to increase entry into cell cycle vs their capacity to increase sensitivity to AID. Our data indicate that IL-2 plays a unique role in the regulation of AID in both Th1 and Th2 subsets and that with a given AID stimulus, cell cycle progression is necessary, but not sufficient, for AID. Interestingly, induction of cell cycle entry and sensitivity to AID can be dissociated (partial signaling) not only with different cytokines, but even with point mutations in IL-2 itself. This provides the first evidence that cytokine variants or pharmacological agents that mimic their action will be useful in enhancing selective elements of pleiotropic cytokine actions.

Animals↗

PubMed1997

Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system.

Mutations of CD95 and CD95L, lpr and gld, respectively, are associated with spontaneous autoimmune disease and alteration of immune privilege. In lpr or gld animals these processes would be expected to exacerbate experimental allergic encephalomyelitis (EAE), an animal model of the autoimmune demyelinating disease multiple sclerosis. However, here we show that the lpr and gld mutations did not overcome the MHC-defined limits of disease and, surprisingly, did not exacerbate the pathology of EAE on a sensitive haplotype. In fact, the mutations dramatically ameliorated clinical signs of EAE without affecting the development of a Th1 response or inflammatory cell infiltration into the central nervous system. Fewer apoptotic cells were detected in inflammatory lesions of lpr mice than in wild-type lesions of similar severity. Our results indicate that CD95L is not an instrumental component of immune privilege in the central nervous system, and that functional CD95 and CD95L are important for the progression of clinical disease.

Animals↗

PubMed1997

Cyclosporine-insensitive partial signaling and multiple roles of Ca2+ in Fas ligand-induced lysis.

The induction of Fas ligand (FasL) mRNA expression and FasL-mediated cytotoxicity in CD8+ CTL is a rapid and transient response to activation via the TCR. This response can also be initiated by pharmacologic activation of two major TCR signaling pathways using phorbol ester (PMA) and calcium ionophore (ionomycin). In these experiments using CD8+ alloreactive cell lines, we demonstrate that induction of FasL mRNA can occur in response to either PMA or ionomycin independently. However, only the ionomycin pathway is sensitive to inhibition by cyclosporine A. Both pathways are blocked by genistein, a general protein tyrosine kinase inhibitor. The magnitude of induction of FasL mRNA is not proportional to the manifested FasL-dependent cytotoxicity. We also found a calcium requirement for cytotoxicity that is unrelated to FasL mRNA induction. In addition to the positive effects of constitutive and induced calcium levels on FasL-mediated cytotoxicity, calcium may play a role in the rapid down-regulation of the response. We also present data suggesting that CD2 and LFA-1 contribute to FasL-mediated cytotoxicity. Together these results suggest pathways by which partial TCR activation could, among the many activation-induced functions of a T cell, selectively lead to the induction of FasL-mediated cytotoxicity that can be regulated by lineage/ activation-dependent accessory molecules on the target.

Animals↗

PubMed1997

Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation.

Graft-versus-host disease (GvHD) is the major limiting toxicity of allogeneic bone marrow transplantation. T cells are important mediators of GvHD, but the molecular mechanisms that they use to induce GvHD are controversial. Three effector pathways have been described for cytotoxic T lymphocytes: one requires perforin and granzymes, the second Fas (APO-1; CD95) and its ligand. Thirdly, secreted molecules (e.g., TNF-alpha, gamma-IFN) can also mediate cytotoxicity. Together, these mechanisms appear to account for virtually all cytotoxicity induced by activated CTL in standard in vitro lytic assays. Using transplants across histocompatibility barriers, we were able to analyze the contributions of these effector molecules to cell-mediated cytotoxicity in vivo in a GvHD model. We found that Fas ligand is an important independent mediator of class II-restricted acute murine GvHD, while perforin/granzyme-dependent mechanisms have only a minor role in that compartment. In contrast, perforin/ granzyme-dependent mechanisms are required for class I-restricted acute murine GvHD, while Fas ligand is not. The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design. In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation.

Animals↗

PubMed1997

Mechanisms responsible for granzyme B-independent cytotoxicity.

Using granzyme B-deficient mice obtained by gene targeting, we previously demonstrated that granzyme B is required for the rapid induction of apoptotic target cell death by cytotoxic T lymphocytes (CTLs); however, CTLs are also equipped with additional effector mechanisms. In the present study, we examined the mechanisms responsible for granzyme B-independent cytotoxicity using in vitro lytic assays with CTLs derived from mice deficient for both granzyme B and Fas ligand (FasL) (granzyme B-/- x gld/gld) or for perforin and FasL (perforin x gld/gld). Our results show that primary mixed lymphocyte reaction (MLR)-derived CTLs from granzyme B-/- x gld/gld mice induce apoptosis of allogeneic targets with less efficiency and a longer delay than CTLs deficient for granzyme B alone. The residual cytotoxicity in granzyme B-/- x gld/gld CTLs is primarily accounted for by a perforin-dependent mechanism, since perforin-/- x gld/gld CTLs have virtually no residual cytotoxic activity in our assays. Granzyme B-independent cytotoxicity is therefore partially accounted for by the Fas pathway and partially by another perforin-dependent mechanism.

Animals↗

PubMed1997

Agonist antibody and Fas ligand mediate different sensitivity to death in the signaling pathways of Fas and cytoplasmic mutants.

We have produced three forms of human Fas: full-length Fas, Fas with a C-terminal deletion, and a chimera between extracellular Fas and the intracellular domain of the tumor necrosis factor receptor I p55 subunit. We transfected cell lines with these constructs to compare the relative capacity of antibody agonists and the physiological Fas ligand (FasL) to stimulate death. With two agonistic antibodies, the chimera is 100- to 1000-fold more sensitive to induction of death than the full-length Fas. The C-terminal deletion mutant also shows greatly enhanced death in comparison to the wild-type receptor. In contrast, when FasL is used to trigger the Fas pathway, wild-type Fas and the deletion mutant are similarly sensitive, whereas the chimera is 100-fold less susceptible to ligand-mediated killing than Fas. This demonstrates that antibody agonists and natural ligand can stimulate different signaling pathways and emphasizes the limitations of defining physiologically important signaling pathways solely by antibody agonists.

Animals↗

PubMed1996

CD95-dependent bystander lysis caused by CD4+ T helper 1 effectors.

CD95-dependent lysis of target cells by CD4+ cells raises important questions of specificity and its potential role in inflammation. Much of what we know about CD95L-dependent killing is in fact bystander killing because the T cells have been previously activated by pharmacologic reagents. In an effort to better understand its significance in a more physiologic setting, we have examined bystander lysis by Th1 cells stimulated by Ag and APC in a murine model system. We find that bystander lysis is readily stimulated by M phi APC but not some epithelial lines, even though they themselves are killed in a CD95-dependent process while serving as APC. Bystander activity requires close proximity between the T cell, the APC, and the bystander target because bystanders are not lysed during coculture in Transwells.

Animals↗

PubMed1996

The role of granzyme B in murine models of acute graft-versus-host disease and graft rejection.

A complete molecular description of the syndromes of graft-versus-host disease (GVHD) and graft rejection could have a significant impact on clinical bone marrow transplantation. Recent in vitro experiments (Heusel et al, Cell 76:977, 1994 and Shresta et al, Proc Natl Acad Sci USA 92:5679, 1995) have shown that the putative mediators of these two syndromes, cytotoxic lymphocytes (CTL) and natural killer (NK) cells, respectively, initiate a program of cell death (apoptosis) in susceptible target tissues in a manner critically dependent on the serine protease Granzyme B (gzm B). In the present study, we have analyzed the phenotype of gzm B-deficient mice using experimental transplant models designed to isolate their CD8+ CTL, CD4+ CTL, and NK compartments. We found a significant impairment in class I-dependent GVHD mediated by gzm B -/- CD8+ CTL, whereas class II-dependent GVHD was not altered using gzm B -/- CD4+ effectors. In a hybrid resistance model, gzm B -/- hosts rejected haplo-identical marrow grafts as efficiently as did their wild-type littermates. This result is surprising in light of a severe defect in the ability of gzm B -/- NK cells to induce apoptosis in susceptible targets in vitro. These in vivo data define significant role for gzm B in cytotoxicity mediated by CD8+ CTL, but not by CD4+ CTL. Furthermore, these results do not support a model of hybrid resistance in which NK cells play a pivotal role.

Animals↗

PubMed1996

Induction of sensitivity to activation-induced death in primary CD4+ cells: a role for interleukin-2 in the negative regulation of responses by mature CD4+ T cells.

We examine the requirements for converting naive, mature CD4+ cells from an activation-induced death (AID)-resistant to a -sensitive phenotype. Priming for sensitivity to AID can be divided into two steps. The first is a mitogen/CD3-dependent, cyclosporin-sensitive signal and the second a cytokine-dependent, cyclosporin-insensitive one. Under these conditions, interleukin (IL)-2, but not IL-4, IL-7 or IL-15, the receptors of which share a common receptor gamma chain, is capable of providing the cytokine signal for inducing sensitivity to AID. Increased expression of the low-affinity IL-2R alpha chain (CD25) is associated with acquisition of AID sensitivity and antibodies to CD25 block acquisition of AID sensitivity in the presence of IL-2. As with T cell hybridomas, AID is dependent on both CD95 and CD95 ligand (CD95L) expression, but unlike hybridomas, the sensitive and resistant phenotypes of primary CD4+ cells cannot be distinguished by levels of CD95 expression, functional CD95L nor the fraction of cells in cycle. The results suggest that the unique function of IL-2 is to regulate proteins, either not important or constitutively regulated in T cell hybridomas, that are essential for cell-autonomous suicide of activated CD4+ cells. These experiments provide a mechanism for the recent observations of chronic lymphoproliferation and autoimmune disease in mice with null mutations in IL-2 or CD25.

Animals↗