Showing papers on "Cytotoxic T cell published in 1994"
TL;DR: Results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.
2,715 citations
TL;DR: It is suggested that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and a role for CTL in protective immunity to HIV- 1 in vivo is indicated.
Abstract: Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.
2,614 citations
TL;DR: Results suggest that the MAb may obstruct the interaction of CTLA-4 with its natural ligand and block a negative signal, or directly signal T cells to down-regulate immune function.
2,086 citations
TL;DR: The cytotoxic action of A beta on neurons results from free radical damage to susceptible cells, suggesting that A beta activates a member of this class of enzymes.
2,060 citations
TL;DR: HIV-1-specific CTL activity is a major component of the host immune response associated with the control of virus replication following primary HIV-1 infection and have important implications for the design of antiviral vaccines.
Abstract: Human immunodeficiency virus type 1 (HIV-1) Env-, Gag-, Pol-, Nef-, and Tat-specific cytotoxic T-lymphocyte (CTL) activities were quantitated temporally in five patients with symptomatic primary HIV-1 infection. A dominant CD8(+)-mediated, major histocompatibility complex class I-restricted CTL response to the HIV-1 envelope glycoprotein, gp160, was noted in four of the five patients studied. The level of HIV-1-specific CTL activity in the five patients paralleled the efficiency of control of primary viremia. Patients who mounted strong gp160-specific CTL responses showed rapid reduction of acute plasma viremia and antigenemia, while in contrast, primary viremia and antigenemia were poorly controlled in patients in whom virus-specific CTL activity was low or undetectable. These results suggest that HIV-1-specific CTL activity is a major component of the host immune response associated with the control of virus replication following primary HIV-1 infection and have important implications for the design of antiviral vaccines.
1,924 citations
TL;DR: The results indicate that lpr and gld are mutations in Fas and Fasl, respectively, and suggest important roles of the Fas system in development of T cells as well as cytotoxic T lymphocyte-mediated cytotoxicity.
1,574 citations
TL;DR: It is shown that CD4+ T cells are dispensable for short-term acute infection in which CD8+ CTL activity does not need to be sustained for more than 2 weeks, but under conditions of chronic infection, in which it takes several months or longer to clear the infection, CD4-cell function is critical.
Abstract: In this study, we have examined the relative contributions of CD4+ and CD8+ T cells in controlling an acute or chronic lymphocytic choriomeningitis virus (LCMV) infection. To study acute infection, we used the LCMV Armstrong strain, which is cleared by adult mice in 8 to 10 days, and to analyze chronic infection, we used a panel of lymphocyte-tropic and macrophage-tropic variants of LCMV that persist in adult mice for several months. We show that CD4+ T cells are not necessary for resolving an acute LCMV infection. CD4+ T-cell-depleted mice were capable of generating an LCMV-specific CD8+ cytotoxic T-lymphocyte (CTL) response and eliminated virus with kinetics similar to those for control mice. The CD8+ CTL response was critical for resolving this infection, since beta 2-microglobulin knockout (CD8-deficient) mice were unable to control the LCMV Armstrong infection and became persistently infected. In striking contrast to the acute infection, even a transient depletion of CD4+ T cells profoundly affected the outcome of infection with the macrophage- and lymphocyte-tropic LCMV variants. Adult mice given a single injection of anti-CD4 monoclonal antibody (GK1.5) at the time of virus challenge became lifelong carriers with high levels of virus in most tissues. Unmanipulated adult mice infected with the different LCMV variants contained virus for prolonged periods (> 3 months) but eventually eliminated infection from most tissues, and all of these mice had LCMV-specific CD8+ CTL responses. Although the level of CTL activity was quite low, it was consistently present in all of the chronically infected mice that eventually resolved the infection. These results clearly show that even in the presence of an overwhelming viral infection of the immune system, CD8+ CTL can remain active for long periods and eventually resolve and/or keep the virus infection in check. In contrast, LCMV-specific CTL responses were completely lost in chronically infected CD4-depleted mice. Taken together, these results show that CD4+ T cells are dispensable for short-term acute infection in which CD8+ CTL activity does not need to be sustained for more than 2 weeks. However, under conditions of chronic infection, in which CD8+ CTLs take several months or longer to clear the infection, CD4+ T-cell function is critical. Thus, CD4+ T cells play an important role in sustaining virus-specific CD8+ CTL during chronic LCMV infection. These findings have implications for chronic viral infections in general and may provide a possible explanation for the loss of human immunodeficiency virus-specific CD8+ CTL activity that is seen during the late stages of AIDS, when CD4+ T cells become limiting.
1,170 citations
TL;DR: The early decision towards Thl and Th2 cells in the immune response is dependent on the balance between IL-12, which favored Thl responses, and IL-4, which favors Th2 responses.
1,097 citations
TL;DR: Two complementary, specific cytotoxic mechanisms are functional in CTLs, one based on the secretion of lytic proteins and one which depends on cell-surface ligand–receptor interaction, which is triggered upon T-cell receptor occupancy and directed to the cognate target cell.
Abstract: The recent generation of perforin knock-out mice has demonstrated a crucial role for the pore-forming perforin in cytolytic T-lymphocyte (CTL)-mediated cytolysis. Perforin-deficient mice failed to clear lymphocytic choriomeningitis virus in vivo, yet substantial killing activity still remained in perforin-free CTLs in vitro, indicating the presence of (a) further lytic pathway(s). Fas is an apoptosis-signalling receptor molecule on the surface of a number of different cells. Here we report that both perforin-deficient and Fas-ligand-deficient CTLs show impaired lytic activity on all target cells tested. The killing activity was completely abolished when both pathways were inactivated by using target cells from Fas-receptor-deficient lpr mice and perforin-free CTL effector cells. Fas-ligand-based killing activity was triggered upon T-cell receptor occupancy and was directed to the cognate target cell. Thus, two complementary, specific cytotoxic mechanisms are functional in CTLs, one based on the secretion of lytic proteins and one which depends on cell-surface ligand-receptor interaction.
1,065 citations
TL;DR: In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.
Abstract: Background Lymphoma associated with Epstein-Barr virus (EBV) is a complication of bone marrow transplantation that responds poorly to standard forms of therapy. The lymphoma is usually of donor origin. We hypothesized that treatment with infusions of donor leukocytes, which contain cytotoxic T cells presensitized to EBV, might be an effective treatment. Methods We studied five patients in whom EBV-associated lymphoproliferative disorders developed after they received a T-cell-depleted allogeneic bone marrow transplant. Biopsy specimens were immunophenotyped, subjected to the polymerase chain reaction to determine the origin of the lymphoma (donor or host) and to detect the presence of EBV, and analyzed by Southern blotting for the presence of the clonal EBV genome and immunoglobulin-gene rearrangement. Patients were treated with infusions of unirradiated donor leukocytes at doses calculated to provide approximately 1.0 × 106 CD3+ T cells per kilogram of body weight. Results Histopathological examination o...
1,064 citations
TL;DR: In this paper, a purified CD1b-restricted antigen of Mycobacterium tuberculosis presented to alpha beta TCR+ T cells is mycolic acid, a family of alpha-branched, beta-hydroxy, long-chain fatty acids found in mycobacteria.
Abstract: Major histocompatibility complex (MHC) class I and class II molecules bind immunogenic peptides and present them to lymphocytes bearing the alpha beta T-cell antigen receptor (TCR). An analogous antigen-presenting function also has been proposed for the non-MHC-encoded CD1 molecules, a family of non-polymorphic, beta 2-microglobulin-associated glycoproteins expressed on most professional antigen-presenting cells. In support of this hypothesis, CD1 molecules are recognized by selected CD4-CD8- alpha beta or gamma delta TCR+ T-cell clones, and we have recently shown that CD1 molecules restrict the recognition of foreign microbial antigens by alpha beta TCR+ T cells. But the substantial structural divergence of CD1 from MHC class I and class II molecules, raises the possibility that the antigens presented by the CD1 system may differ fundamentally from those presented by MHC-encoded molecules. Here we report that a purified CD1b-restricted antigen of Mycobacterium tuberculosis presented to alpha beta TCR+ T cells is mycolic acid, a family of alpha-branched, beta-hydroxy, long-chain fatty acids found in mycobacteria. This example of non-protein microbial antigen recognition suggests that alpha beta TCR+ T cells recognize a broader range of antigens than previously appreciated and that at least one member of the CD1 family has evolved the ability to present lipid antigens.
TL;DR: Melanoma-specific CTLs had an exceptionally high affinity for this nine-residue peptide, which reconstituted an epitope for CTL lines from each of five different melanoma patients tested.
Abstract: Of several thousand peptides presented by the major histocompatibility molecule HLA-A2.1, at least nine are recognized by melanoma-specific cytotoxic T lymphocytes (CTLs). Tandem mass spectrometry was used to identify and to sequence one of these peptide epitopes. Melanoma-specific CTLs had an exceptionally high affinity for this nine-residue peptide, which reconstituted an epitope for CTL lines from each of five different melanoma patients tested. Recognition by multiple CTL lines suggests that this may be a promising candidate for use in peptide-based melanoma vaccines.
TL;DR: It is concluded that gzm B serves a critical and nonredundant role for the rapid induction of target cell DNA fragmentation and apoptosis by alloreactive cytotoxic T lymphocytes.
TL;DR: The response capabilities of T cells are more flexible than originally believed, and much of this flexibility comes from the interplay of TCR signals and signs from the environment.
Journal Article•
TL;DR: The data suggest that holes in the functional T cell repertoire, if they exist, may be relatively rare and correlate well with class I binding affinity measurements of either naturally processed peptides or previously described T cell epitopes.
Abstract: The relationship between binding affinity for HLA class I molecules and immunogenicity of discrete peptide epitopes has been analyzed in two different experimental approaches. In the first approach, the immunogenicity of potential epitopes ranging in MHC binding affinity over a 10,000-fold range was analyzed in HLA-A*0201 transgenic mice. In the second approach, the antigenicity of approximately 100 different hepatitis B virus (HBV)-derived potential epitopes, all carrying A*0201 binding motifs, was assessed by using PBL of acute hepatitis patients. In both cases, it was found that an affinity threshold of approximately 500 nM (preferably 50 nM or less) apparently determines the capacity of a peptide epitope to elicit a CTL response. These data correlate well with class I binding affinity measurements of either naturally processed peptides or previously described T cell epitopes. Taken together, these data have important implications for the selection of epitopes for peptide-based vaccines, and also formally demonstrate the crucial role of determinant selection in the shaping of T cell responses. Because in most (but not all) cases, high affinity peptides seem to be immunogenic, our data also suggest that holes in the functional T cell repertoire, if they exist, may be relatively rare.
TL;DR: Results recently obtained in NOD mice indicate that the goal of nontoxic long-lasting immune protection from the disease is feasible if treatment is started early enough and before putative etiological agents are identified, one must base immunotherapy on nonantigen-specific agents.
Abstract: IDDM is unquestionably an autoimmune disease, as reflected by the presence of beta-cell-reactive autoantibodies and T cells, T cell-mediated transfer of the disease in nondiabetic mice, rats, and humans, and disease sensitivity to immunosuppressive therapy. T cells are predominantly, if not exclusively, involved in creating the islet lesions that lead to beta-cell atrophy after a stage of reversible inflammation. A full understanding of the disease pathogenesis will require a better definition of the nature of the triggering and target autoantigen(s) and of the effector mechanisms (cytokines, cytotoxic cells?). Much less information is available on the etiology than on the pathogenesis. Genetic factors are mandatory and the involvement of predisposition genes (HLA and non-HLA) is now being unravelled. The modulatory role of environmental factors is demonstrated by the high disease discordance rate in identical twins and by experimental data showing positive and negative modulation of the disease by a number of agents, notably infectious agents and food constituents. It is not clear, however, whether a given environmental factor, e.g. a precise virus or a cow's milk component, plays a real etiological role in a selected genetic background. IDDM thus appears as a multifactorial disease. It is not known, however, whether all factors intervene concomitantly in a given individual or separately in subsets of patients, explaining the clinical heterogeneity of the disease. The mechanisms underlying the loss of tolerance to self beta-cell autoantigen(s) are still unknown. Defective intrathymic negative selection of autoantigen-specific autoreactive T cell clones is unlikely. Breakdown of T cell anergy could occur according to various mechanisms, including aberrant expression of MHC molecules and molecular mimicry. Defective suppressor T cell function, perhaps related to TH1/TH2 imbalance, probably intervenes by amplifying the anti-beta-cell autoimmune response whatever its triggering mechanism. Before putative etiological agents are identified, one must base immunotherapy on nonantigen-specific agents. Results recently obtained in NOD mice indicate that the goal of nontoxic long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced. This double strategy (early intervention, tolerance induction) is the main challenge for immunodiabetologists.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: To determine whether T cells, like B cells, can become clonally expanded in normal individuals as a function of age, the T cell V beta repertoire of cord blood to that of peripheral blood from normal donors over 65 yr of age was compared.
Abstract: To determine whether T cells, like B cells, can become clonally expanded in normal individuals as a function of age, we compared the T cell V beta repertoire of cord blood to that of peripheral blood from normal donors over 65 yr of age. T cells from elderly subjects contained expanded subsets (greater than the mean+three standard deviations) of T cell receptor (TCR) V beta populations. These expanded subsets were observed primarily among CD8, but not CD4 cells, represented up to 37.5% of all CD8 cells, and were present in most elderly subjects. An expanded V beta 5.2/3 CD8 subset and a V beta 6.7a CD8 subset from separate donors were analyzed by reverse transcriptase-polymerase chain reaction, cloning and sequencing of the TCR beta chain VDJ junction. In both cases the expanded subsets were mono- or oligoclonal while control CD4 populations were polyclonal. Using two-color flow cytometry it was possible to identify the expanded V beta 6.7a subset as CD8+ CD28-CD11b+ cells. In three of five random old subjects similar expansions of V beta subsets were found specifically in the CD8+ CD28- subpopulation, an interesting subset of cytotoxic T lymphocytes, known to lack proliferative responses to TCR stimuli. It is common practice to use the demonstration of clonality as a diagnostic indicator for T cell lymphoma/leukemia. In view of the high frequency of expanded T clones of T cells in normal elderly subjects the diagnostic usefulness of this test should be reexamined.
TL;DR: The fas gene plays an essential role in activation-induced cell death in mature T lymphocytes, but not in the negative selection of immature cells in the thymus in MRL-lpr/lpr and MRL+/+ strains.
TL;DR: It is shown that memory CD8+ cytotoxic T lymphocytes persist indefinitely in the absence of priming antigen, retain the memory phenotype (CD44hi), and provide protection against virus challenge.
Abstract: Memory is a hallmark of the immune system and ever since its recognition there has been considerable interest in understanding how immunity is maintained. The current model is that long-term memory is dependent on persistent antigenic stimulation. We report here results that challenge this view and provide evidence that antigen is not essential for the maintenance of CD8+ T-cell memory. We show that memory CD8+ cytotoxic T lymphocytes persist indefinitely in the absence of priming antigen, retain the memory phenotype (CD44hi), and provide protection against virus challenge. These findings suggest a re-evaluation of our current thinking on mechanisms involved in maintaining immunity and have implications towards designing effective vaccination strategies.
TL;DR: Responses mediated by CD4+ cells per se were insufficient to mediate destruction of hepatocytes in vivo, despite the activation of virus-specific T helper cells of Th1 subsets.
TL;DR: Major oligoclonal expansions of these CD8+ T lymphocytes may represent an important component of the primary immune response to viral infections and may help to clarify both the immunopathogenic and the protective mechanisms of HIV infection.
Abstract: A SIGNIFICANT proportion (up to 70%) of individuals experience an acute clinical syndrome of varying severity associated with primary infection with the human immunodeficiency virus (HIV). We report here studies on six individuals who showed an acute HIV syndrome which generally resolved within four weeks, concomitant with a dramatic downregulation of viraemia. To characterize the T-cell-mediated primary immune response to HIV, we used combined semiquantitative polymerase chain reaction assay and cytofluorometry to analyse the T-cell antigen receptor repertoire in sequential peripheral blood mononuclear cells from the patients. We found major oligoclonal expansions in a restricted set of variable-domain beta-chain (V beta) families. Cells expressing the expanded V beta s predominantly expressed the CD8 T-cell differentiation antigen and mediated HIV-specific cytotoxicity. Major oligoclonal expansions of these CD8+ T lymphocytes may represent an important component of the primary immune response to viral infections and may help to clarify both the immunopathogenic and the protective mechanisms of HIV infection.
TL;DR: It is shown here that activated gamma delta T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF), which suggests that intraepithelial alpha beta T cells function in surveillance and in repair of damaged epithelial tissues.
Abstract: The role played in immune surveillance by gamma delta T cells residing in various epithelia has not been clear. It is shown here that activated gamma delta T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF). In contrast, intraepithelial alpha beta T cells, as well as all lymphoid alpha beta and gamma delta T cell populations tested, did not produce KGF or promote the growth of cultured epithelial cells. These results suggest that intraepithelial gamma delta T cells function in surveillance and in repair of damaged epithelial tissues.
TL;DR: Results indicate that the cells of the skin can take up and express free foreign DNA and induce cellular and humoral immune responses against the encoded protein, and suggest that DNA uptake by the skin-associated lymphoid tissues may play a role in the induction of cytotoxic T cells against viruses and other intracellular pathogens.
Abstract: The skin and mucous membranes are the anatomical sites were most viruses are first encountered by the immune system. Previous experiments have suggested that striated muscle cells are unique among mammalian cell types in their capacity to take up and express free DNA in the absence of a viral vector or physical carrier. However, we have found that mice injected into the superficial skin with free (naked) plasmid DNA encoding the influenza nucleoprotein gene had discrete foci of epidermal and dermal cells, including cells with dendritic morphology, that contained immunoreactive nucleoprotein antigen. A single intradermal administration of 0.3-15 micrograms of free plasmid DNA induced anti-nucleoprotein-specific antibody and cytotoxic T lymphocytes that persisted for at least 68-70 weeks after vaccination. Intradermal gene administration induced higher antibody titers than did direct gene injection into skeletal muscle and did not cause local inflammation or necrosis. Compared with control animals, the gene-injected mice were resistant to challenge with a heterologous strain of influenza virus. These results indicate that the cells of the skin can take up and express free foreign DNA and induce cellular and humoral immune responses against the encoded protein. We suggest that DNA uptake by the skin-associated lymphoid tissues may play a role in the induction of cytotoxic T cells against viruses and other intracellular pathogens.
TL;DR: Gene targeting of this receptor confirms its role in the lethality attributable to low doses of lipopolysaccharide after sensitization with D-galactosamine and shows a dramatic decrease in tissue necrosis, indicating that this receptor plays a roles in the necrotic effects of TNF.
Abstract: TUMOUR necrosis factor (TNF) elicits multiple biological effects through two distinct cell surface receptors, TNF-R1 (p55) and TNF-R2 (p75). Most TNF-mediated biological responses, such as cell death, gene induction, antiviral activity and cytokine production, have been attributed to TNF-R1 (refs 1–5). Gene targeting of this receptor confirms its role in the lethality attributable to low doses of lipopolysaccharide after sensitization with D-galactosamine6,7; surprisingly, the toxicity of high doses of lipopolysaccharide was unaffected. The function of TNF-R2 is less well understood, although there are data supporting a role in T-cell development and the proliferation of cytotoxic T lymphocytes8,9. To clarify the physiological role of TNF-R2, we have generated mice deficient in this receptor by gene targeting. The TNF-R2−/− mice show normal T-cell development and activity, but we find that they have increased resistance to TNF-induced death. Additionally, such mice injected subcutaneously with TNF show a dramatic decrease in tissue necrosis, indicating that this receptor plays a role in the necrotic effects of TNF.
TL;DR: These data demonstrate that the melanocyte differentiation antigen gp100 can be recognized in the context of HLA-A2.1 by CTL from a melanoma patient, and may constitute a useful target for specific immunotherapy against melanoma, provided that no unacceptable cytotoxicity towards normal tissue is observed.
Abstract: We recently isolated a cDNA clone that encodes the melanocyte lineage-specific antigen glycoprotein (gp)100. Antibodies directed against gp100 are an important tool in the diagnosis of human melanoma. Since the gp100 antigen is highly expressed in melanocytic cells, we investigated whether this antigen might serve as a target for antimelanoma cytotoxic T lymphocytes (CTL). Here, we demonstrate that cytotoxic tumor-infiltrating lymphocytes (TIL) derived from a melanoma patient (TIL 1200) are directed against gp100. HLA-A2.1+ melanoma cells are lysed by TIL from this patient. In addition, murine double transfectants, expressing both HLA-A2.1 and gp100, are lysed by TIL 1200, whereas transfectants expressing only HLA-A2.1 are not susceptible to lysis. Furthermore, the HLA-A2.1+ melanoma cell line BLM, which lacks gp100 expression and is resistant to lysis, becomes susceptible after transfection of gp100 cDNA. Finally, HLA-A2.1+ normal melanocytes are lysed by TIL 1200. These data demonstrate that the melanocyte differentiation antigen gp100 can be recognized in the context of HLA-A2.1 by CTL from a melanoma patient. Gp100 may therefore constitute a useful target for specific immunotherapy against melanoma, provided that no unacceptable cytotoxicity towards normal tissue is observed.
TL;DR: It is suggested that, as with antigen presentation by MHC class II molecules, presentation by HSPs is also carried out primarily by the host antigen-presenting cells, and this mechanism explains the phenomenon of cross-priming.
Abstract: Recently emerging evidence indicates that the heat shock proteins (HSPs) gp96, hsp90, and hsp70 associate with antigenic peptides derived from cellular proteins. This evidence forms the basis of the following two hypotheses: 1) that HSPs constitute a relay line in which the peptides, after generation in the cytosol by the action of proteases, are transferred from one HSP to another, until they are finally accepted by MHC class I molecules in the endoplasmic reticulum, and 2) that the binding of peptides by HSPs constitutes a key step in the priming of cytotoxic T lymphocytes (CTLs) in vivo. The following chain of events is suggested: HSPs are released from virus-infected cells or tumor cells in vivo during lysis of cells during infection or by the action of antibodies or nonspecific effectors. The HSPs, which are now complexed with antigenic peptides derived from the cognate cells, are taken up by macrophage or other specialized antigen-presenting cells, possibly by a receptor-mediated mechanism. The HSP-borne peptide is then routed to the endogenous presentation pathway in the antigen-presenting cell and is displayed in the context of that cell's MHC class I, where it is finally recognized by the precursor CTLs. Thus it is suggested that, as with antigen presentation by MHC class II molecules, presentation by MHC class I molecules is also carried out primarily by the host antigen-presenting cells. This mechanism explains the phenomenon of cross-priming and has implications for the development of immunological strategies against cancer and infectious diseases.
TL;DR: Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to onedominated by the protective cytokines produced by Th2- like T cells may have applicability to the therapy of certain human autoimmune diseases.
Abstract: The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.
TL;DR: By expressing ICP47, HSV can evade detection by CD8+ T lymphocytes, perhaps explaining the predominance of CD4+ rather thanCD8+ HSV-specific CTLs in vivo.
Journal Article•
TL;DR: The demonstration of altered in vitro apoptosis of lymphocytes derived from SLE patients raises the possibility that abnormalities of apoptosis may contribute to the pathogenesis of SLE.
Abstract: SLE is a disease characterized by the generation of an immune response to intact nuclear Ags, especially components of the nucleosome, histones and DNA. The process of programmed cell death, or apoptosis, is characterized by cleavage of chromatin into oligonucleosomes and release of these nucleosomes into the extracellular space. To address the question of whether altered apoptosis might provide a source of extracellular nuclear Ags in SLE, we have examined apoptosis of lymphocytes isolated from patients with SLE, patients with rheumatoid arthritis (RA), and normal controls. Apoptosis was measured by three independent methods and confirmed by gel electrophoresis. Freshly isolated lymphocytes (t0) showed low levels of apoptosis. However, lymphocytes from SLE patients demonstrated a significant increase in the number of apoptotic cells at t0 compared with normal controls and RA patients. In tissue culture, lymphocytes from all patient groups underwent apoptosis, but the rate of apoptosis of lymphocytes derived from SLE patients was 2.35-fold faster than apoptosis of lymphocytes from normal controls or RA patients. The increased rate of apoptosis could not be accounted for by corticosteroid or cytotoxic medication. There was a significant correlation between SLE disease activity as measured by the systemic lupus activity measure and rate of apoptosis in vitro. The release of intact nucleosomes during apoptosis was measured by ELISA; lymphocytes from SLE patients released increased amounts of nucleosomal material into the extracellular space in direct proportion to the rate of apoptosis. Abnormal apoptosis of lymphocytes in SLE may provide a source of extracellular nuclear Ag to drive the immune response and to allow the formation of immune complexes. The demonstration of altered in vitro apoptosis of lymphocytes derived from SLE patients raises the possibility that abnormalities of apoptosis may contribute to the pathogenesis of SLE.