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Biomedical subjects

R M Zinkernagel

Publications and source records attributed to R M Zinkernagel.

At least 19 recordsLinked to original sources
PubMed2001

Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies.

Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are initiated by extracerebral exposure to prions. Although prion transmission from extracerebral sites to the brain represents a potential target for prophylaxis, attempts at vaccination have been limited by the poor immunogenicity of prion proteins. To circumvent this, we expressed an anti-prion protein (anti-PrP) mu chain in Prnp(o/o) mice. Transgenic mice developed sustained anti-PrP titers, which were not suppressed by introduction of Prnp+ alleles. Transgene expression prevented pathogenesis of prions introduced by intraperitoneal injection in the spleen and brain. Expression of endogenous PrP (PrP(C)) in the spleen and brain was unaffected, suggesting that immunity was responsible for protection. This indicates the feasibility of immunological inhibition of prion disease in vivo.

Amyloid↗
PubMed2001

Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine.

BACKGROUND: Leflunomide is an isoxazol derivative with immunosuppressive capacities in various experimental allo- and xenotransplantation models. Two main mechanisms of action have been described: Inhibition of pyrimidine de novo synthesis and impairment of tyrosine phosphorylation of different tyrosine kinases involved in receptor signaling via B cell and cytokine receptors. MATERIALS AND METHODS: Interference of Leflunomide with the IgM antibody responses to vesicular stomatitis virus (VSV, T-independent type 1), IgM to recombinant VSV glycoprotein (T-independent type 2), and IgG to lymphocytic choriomeningitis virus (LCMV, T-dependent) were analyzed whereas the cytotoxic T cell (CTL) response was examined after LCMV infection. Interference with the CD8+ T cell-mediated autoimmune diabetes in a transgenic mouse expressing the LCMV-glycoprotein in the pancreatic islets was studied as a model for T cell-mediated autoimmune diseases. Uridine substitution experiments were performed to differentiate between the above mentioned two mechanisms of action on different functions of the immune system in vivo. RESULTS: Leflunomide at 35 mg/kg/day suppressed the humoral immune response against all antigens tested. Similar effects on T-independent compared to T-dependent antibody responses required two to four times higher drug doses. CTL responses to LCMV were considerably impaired. Uridine substitution prevented lethal VSV encephalitis under Leflunomide treatment by restoring the neutralizing IgM and IgG responses. However, the inhibition of LCMV specific CTLs and suppression of CD8+ T cell-mediated autoimmune diabetes remained unaffected by additional uridine treatment. CONCLUSIONS: Leflunomide-mediated suppression of B cell and T helper cell activity but not of CTLs largely depends on inhibition of pyrimidine de novo synthesis.

Animals↗
PubMed2001

Regulation of the immune response by antigen.

How, why, and when specific T and B lymphocytes respond against infection follow explicit rules, but how this can be assessed experimentally depends crucially on the methodology used. In this Viewpoint, we discuss the parameters of receptor specificity and antigen that determine whether an immune response can be accurately measured against model antigens and how this relates to protection against a given pathogen. We suggest that antigen structure, localization, dose, and time during which antigen is available are all decisive factors in regulating an immune response.

Animals↗
PubMed2001

Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction.

The vertebrate immune system has evolved to protect against infections that threaten survival before reproduction. Clinically manifest tumours mostly arise after the reproductive years and somatic mutations allow even otherwise antigenic tumours to evade the attention of the immune system. Moreover, the lack of immunological co-stimulatory molecules on solid tumours could result in T-cell tolerance; that is, the failure of T cells to respond. However, this may not generally apply. Here we report several important findings regarding the immune response to tumours, on the basis of studies of several tumour types. First, tumour-specific induction of protective cytotoxic T cells (CTLs) depends on sufficient tumour cells reaching secondary lymphatic organs early and for a long enough duration. Second, diffusely invading systemic tumours delete CTLs. Third, tumours that stay strictly outside secondary lymphatic organs, or that are within these organs but separated from T cells by barriers, are ignored by T cells but do not delete them. Fourth, co-stimulatory molecules on tumour cells do not influence CTL priming but enhance primed CTL responses in peripheral solid tumours. Last, cross priming of CTLs by tumour antigens, mediated by major histocompatibility complex (MHC) class I molecules of antigen-presenting host cells, is inefficient and not protective. These rules of T-cell induction and maintenance not only change previous views but also rationales for anti-tumour immunotherapy.

Animals↗
PubMed2001

Rapid peptide turnover and inefficient presentation of exogenous antigen critically limit the activation of self-reactive CTL by dendritic cells.

This study evaluated to what extent presentation of exogenously acquired self-Ags via MHC class I molecules on DC might contribute to the activation of self-reactive CTL and subsequent development of autoimmune disease. We show here by using the rat insulin promotor lymphocytic choriomeningitis virus glycoprotein model of autoimmune diabetes that the activation of self-reactive CTL by DC after uptake of exogenous Ag is very limited, first by the short half-life of MHC class I-associated peptides on DC in vitro and in vivo, and second by the rather inefficient MHC class I presentation of cell-associated self-Ags by DC. These two mechanisms are probably crucial in establishing high thresholds for the induction of self-reactive CTL that prevent autoimmune sequelae after release of sequestered and previously immunologically ignored tissue Ags.

Amino Acid Sequence↗
PubMed2001

Hypercholesterolemia exacerbates virus-induced immunopathologic liver disease via suppression of antiviral cytotoxic T cell responses.

The immune system has to be optimally balanced to be highly effective against infections with cytopathic microbial pathogens and must guarantee efficient destruction of cells infected with noncytopathic agents while leaving the integrity of noninfected cells largely unaltered. We describe here the effects of genetically induced hypercholesterolemia on cellular immunity in apolipoprotein E (ApoE(-/-)) and low density lipoprotein receptor-deficient (LDLR(-/-)) mice during infection with the hepatotropic lymphocytic choriomeningitis virus WE strain. In both ApoE(-/-) and LDLR(-/-) mice hypercholesterolemia aggravated virus-induced immunopathologic liver disease. ApoE(-/-) mice exhibited a higher susceptibility to virus-induced immunopathology than LDLR(-/-) mice and usually succumbed to immunopathologic disease when infected with high doses of virus. Initial virus spread was not influenced by the hypercholesterolemia, whereas clearance of the virus from spleen and nonlymphoid organs, including liver, was delayed. Activation of antiviral CTL, measured by ex vivo cytotoxicity and IFN-gamma production, and recruitment of specific CTL into blood and liver were impaired in hypercholesterolemic mice, indicating that hypercholesterolemia had a significant suppressive effect on cellular immunity. Taken together, these data provide evidence that hypercholesterolemia suppresses antiviral immune responses, thereby changing the host-virus balance, and can increase susceptibility to acute or chronic and potentially lethal virus-induced immunopathologic disease. These findings impinge on our understanding of hypercholesterolemia as a disease parameter and may explain aspects of the frequent association of persistent pathogens with hypercholesterolemia-induced diseases, such as atherosclerosis.

Animals↗
PubMed2001

Intralymphatic immunization enhances DNA vaccination.

Although DNA vaccines have been shown to elicit potent immune responses in animal models, initial clinical trials in humans have been disappointing, highlighting a need to optimize their immunogenicity. Naked DNA vaccines are usually administered either i.m. or intradermally. The current study shows that immunization with naked DNA by direct injection into a peripheral lymph node enhances immunogenicity by 100- to 1,000-fold, inducing strong and biologically relevant CD8(+) cytotoxic T lymphocyte responses. Because injection directly into a lymph node is a rapid and easy procedure in humans, these results have important clinical implications for DNA vaccination.

Animals↗
PubMed2001

Impairment of CD4(+) T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants.

We have shown previously that neutralizing antibodies (nAbs) are important contributors to the long-term immune control of lymphocytic choriomeningitis virus infection, particularly if cytotoxic T cell responses are low or absent. Nevertheless, virus escape from the nAb response due to mutations within the surface glycoprotein gene may subsequently allow the virus to persist. Here we show that most of the antibody-escape viral mutants retain their immunogenicity. We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4(+) T cell responsiveness during the establishment of viral persistence. Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

Animals↗
PubMed2001

Perforin-independent regulation of dendritic cell homeostasis by CD8(+) T cells in vivo: implications for adaptive immunotherapy.

We investigated here the effects of perforin on CTL responses during interaction of dendritic cells (DC) with cytotoxic T lymphocytes in vivo. Using MHC class I tetramers complexed with the immunodominant CTL epitope of the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP33), we followed the kinetics of DC-induced CTL responses. GP33-presenting DC induced rapid primary expansion of both perforin-competent and -deficient CTL with similar kinetics. Secondary CTL responses in perforin-deficient and normal control mice after DC-booster immunization were more rapid than the primary responses, but never reached the high initial levels, suggesting that reactivated memory CTL eliminated the antigen-presenting DC and thereby limited the booster effect. Whereas killingof DC in vitro was strictly dependent on perforin, elimination of GP33-presenting DC by CTL in vivo was largely independent of perforin and Fas. Taken together, these results suggest that control of DC homeostasis by CTL, i. e. elimination of DC by the effector cells they had elicited, is controlled via multiple and probably redundant signals and represents an important fail-safe mechanism to avoid exaggerated CTL responses.

Animals↗
PubMed2001

Viral escape from the neutralizing antibody response: the lymphocytic choriomeningitis virus model.

In addition to CD8+ cytotoxic T lymphocyte (CTL) responses, neutralizing antibodies contribute substantially to the long-term immune control of noncytopathic viruses, as demonstrated during infection with the lymphocytic choriomeningitis virus (LCMV). The high virus load during the initial phase of an infection and the ability of this RNA virus to spontaneously acquire mutations are important prerequisites for escaping an ongoing immune response. In this context, LCMV escape from the humoral response by single point mutations in neutralizing envelope protein determinants may occur, particularly during conditions of CTL deficiency, leading to virus persistence.

Animals↗
PubMed2001

Dendritic cells in autoimmune diseases.

Subclinical autoimmune responses can be frequently detected in healthy individuals. Sustained activation of autoreactive lymphocytes is, however, required for the development of autoimmune diseases associated with ongoing tissue destruction either in single organs or generalized with multiple manifestations. Clinical and experimental evidence suggests that prolonged presentation of self antigens by dendritic cells is crucial for the development of destructive autoimmune disease. We discuss here a simplified threshold model where the key parameters for the magnitude of the autoimmune response are the amount of previously ignored self peptides presented by dendritic cells and the duration of the antigen presentation in secondary lymphoid organs. Multiple factors influence the threshold for the conversion of an autoimmune response to overt autoimmune disease. Frequent or persistent viral infections of the target organ may favor autoimmune disease by increasing the amounts of released self antigens, generating cytokine-mediated bystander activation of self-reactive lymphocytes and/or sustaining a chronic response via neoformation of lymphoid structures in the target organ.

Animals↗
PubMed2001

Transplantation tolerance from a historical perspective.

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.

Animals↗
PubMed2001

Complement facilitates early prion pathogenesis.

New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.

Animals↗