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E Heber-Katz

Publications and source records attributed to E Heber-Katz.

At least 55 records · Page 3Linked to original sources
PubMed1989

Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar V alpha and V beta chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different.

Prospects for specific immune intervention in T cell-mediated autoimmune disease via anti-idiotypic regulation depend on the degree of diversity of the responder cell antigen receptor repertoire. A highly heterogenous response against self epitopes offers little chance for such regulation. We report here that the Lewis rat autoimmune disease experimental allergic encephalomyelitis, generally considered to be a model of human multiple sclerosis, is caused by T cells that use a limited set of TCR V genes. We have cloned the rat TCR alpha and beta chain cDNAs from the Lewis rat x mouse T cell hybridoma 510, which retains the rat specificity for the encephalitogenic determinant of myelin basic protein (MBP). Using Northern blot analysis of T cell RNA with the cloned V region probes, we have found a specific, and near perfect, correlation between expression of TCR message hybridizing to the V alpha 510 and VB510 probes and specificity for the encephalitogenic determinant of MBP in both T cell hybridomas and encephalitogenic T cell clones. This restricted V gene usage provides a basis for observed idiotypic regulation of auto-reactive T cells, and possible therapy for autoimmune disease. A curious and unexplained observation is that the Lewis rat V alpha/V beta combination that dominates the encephalitogenic response to the 68-88 peptide of MBP is precisely the same V alpha/V beta combination used by the B10.PL mouse response to the encephalitogenic response to the 1-9 peptide of MBP.

Amino Acid Sequence↗
PubMed1989

The V-region disease hypothesis: evidence from autoimmune encephalomyelitis.

Experimental allergic encephalomyelitis has been shown to have an immunological basis. In fact, the disease can be induced by T cells specific for myelin basic protein, a molecule found in abundance in the central nervous system. In this article, Ellen Heber-Katz and Hans Acha-Orbea discuss the T-cell receptor (TCR) repertoire of the encephalitogenic T-cell response, and show that a limited V gene pool, in fact a single V beta and two V alpha families, are being used by the PL/J and B10.PL mice and by every rat strain examined, even though the antigenic determinants and the major histocompatibility complex (MHC) molecules are different in all cases. This extraordinary finding suggests that the TCR is involved in encephalitogenicity in a way that not only involves the recognition of antigen in association with MHC, but also as an effector molecule that results in encephalitis. If this is true, it implies that TCRs, in general, play more than one role in mammalian physiology.

Amino Acid Sequence↗
PubMed1988

Antigen presenting function of class II MHC expressing pancreatic beta cells.

Class II major histocompatibility complex (MHC) gene expression in the mouse is generally limited to thymic epithelium and bone marrow-derived cells such as B lymphocytes and cells of the macrophage/dendritic cell lineage (M phi/DC). Class II-bearing B lymphocytes and M phi/DC possess antigen presenting cell (APC) function; that is, they can stimulate T lymphocytes reactive to either antigen plus MHC or foreign MHC alone. To assess whether non-bone-marrow-derived cells can acquire APC function and elicit graft rejection through expression of class II, we studied transgenic pancreatic islet beta cells that express a foreign class II (I-E) molecule. In vivo, grafts of I-E+ transgenic islets into I-E- naive hosts are not rejected unless the host is primed by an injection of I-E+ spleen cells. In vitro, the I-E+ beta cells are unable to stimulate T lymphocytes reactive to I-E plus a peptide antigen. Paradoxically, they induce antigen specific unresponsiveness in the T cells. We propose that expression of class II on non-lymphoid cells may serve as an extrathymic mechanism for maintaining self tolerance.

Animals↗
PubMed1988

Protection from experimental allergic encephalomyelitis conferred by a monoclonal antibody directed against a shared idiotype on rat T cell receptors specific for myelin basic protein.

Immunizing Lewis rats with guinea pig myelin basic protein (MBP) yielded an encephalitogen specific, Ia-restricted, rat-mouse T cell hybridoma 5.10, which was used to establish a clonotypic mAb (10.18) that binds to and precipitates the rat TCR. By two-dimensional gel electrophoresis, the rat TCR was shown to consist of two disulfide-linked peptide chains with mol wt of 48,000 and 39,000. 10.18 binds the majority of cells in MBP-specific T cell lines that are capable of transferring experimental allergic encephalomyelitis (EAE) to Lewis rat recipients, but does not bind to either a purified protein derivative of tuberculin-specific cell line or an OVA-specific line. Furthermore, soluble 10.18 can block antigen-specific stimulation of hybridoma 5.10 but cannot control hybridomas, while immobilized 10.18 stimulates 5.10, but cannot control the hybrids. Though 10.18+ cells are very rare in normal rats, increase of 10.18+ cells is observed in MBP-primed paralyzed rats. Finally, when 10.18 is injected into MBP-primed Lewis rats, EAE is abrogated. We have thus characterized EAE as a "mono-idiotypic" autoimmune disease.

Animals↗
PubMed1988

Genetic control of the development of experimental allergic encephalomyelitis in rats. Separation of MHC and non-MHC gene effects.

Experimental allergic encephalomyelitis (EAE)-susceptible Lew and EAE-resistant Brown Norway (BN) rats and the corresponding MHC congenic strains were examined for their ability to develop clinical and histologic EAE. The ability of T cells from these animals to proliferate in vitro in response to whole guinea pig (GP) myelin basic protein (MBP), rat MBP, and to the major encephalitogenic peptide of GP MBP 66-88 (GP 68-88) was also assessed. We found that Lewis (Lew) was highly susceptible and showed good T cell responses to GP, MBP, rat MBP, and GP 68-88. Lew.1N (BN MHC on Lew background) and BN were not susceptible and T cells from these strains showed significant responses to GP MBP, but not to rat MBP or GP 68-88. Although BN.B1 (Lew MHC on BN background) was not susceptible to actively induced EAE, MBP-specific Lew T cells could transfer severe disease to BN.B1. BN.B1 T cells showed responses to GP-MBP, rat MBP, and GP 68-88 and, when transferred to naive BN.B1 or Lew, induced only mild clinical EAE in both strains. Increasing the number of T cells from BN.B1 had no effect on the severity of clinical symptoms in either recipient, suggesting some deficiency in the T cell repertoire that is necessary for induction of severe EAE. These results suggest that 1) the T cell response to rat MBP and GP68-88 (but not to sites other than 68-88 in GP MBP) is necessary for susceptibility to EAE; 2) the ability to respond to both rat MBP and GP 68-88 is determined by the MHC gene products on APC; and 3) given a permissive MHC, the T cell response that results in EAE is influenced by non-MHC genes.

Animals↗
PubMed1988

Overlapping T cell antigenic sites on a synthetic peptide fragment from herpes simplex virus glycoprotein D, the degenerate MHC restriction elicited, and functional evidence for antigen-Ia interaction.

Analysis of the B10.A T cell response to synthetic peptides representing the NH2-terminal 23 amino acids from the HSV glycoprotein D sequence revealed two antigenic determinants for T cells: one localized between residues 1-16 and the other between residues 8-23. The 1-16 site, which is helical, was recognized in the context of the Ia molecule, whereas the 8-23 site, which is nonhelical, was recognized in the context of the I-E molecule. The I-E-restricted response was found to be highly MHC degenerate in that T cell hybridomas specific for the 8-23 peptide responded to antigen on APCs derived from B10.A, B10.A(5R), and B10.A(9R) mice and showed differences in antigenic fine specificity with APCs of different haplotypes. These data support the idea of antigen-Ia interaction.

Amino Acid Sequence↗
PubMed1988

Differences in the repertoire of the Lewis rat T cell response to self and non-self myelin basic proteins.

We have examined the fine specificity of a panel of cloned T cell hybridomas generated from Lewis rats immunized with guinea pig (GP) or Lewis rat myelin basic protein (MBP) to determine the autoimmune T cell repertoire that develops in experimental allergic encephalomyelitis (EAE). This analysis has demonstrated that GP MBP, which was approximately 10-fold more potent for EAE induction than the autologous rat MBP, produced a population in which almost one-fourth of the members responded to GP-unique determinants and displayed no crossreactivity on the self antigen. The remaining majority of GP MBP-induced clones were specific for the 68-88 encephalitogenic determinant and could be subdivided into three groups based on their varying responses to the 68-88 peptide and rat and rabbit MBPs. Surprisingly, one of these groups showed equal reactivity to GP and rat MBPs. In contrast, the clonotype composition of the T cell population induced by rat MBP was quite different. One-half of these clones comprised a single group responding to the 68-88 determinant, reacting equally with GP and rat MBP. All of these responded to the same range of antigen concentrations as their GP-induced counterparts. The remaining half of that population contained a collection of clones that was nearly as encephalitogenic as the 68-88 population after propagation as a short-term T cell line. These clones were specific for at least three distinct antigenic determinants, all displaying extensive cross-species reactivity, and required as little or less rat MBP for maximal stimulation as did the 68-88-reactive clones. We therefore conclude that the T cell repertoire for MBP does include clones with reactivity to both 68-88 and non-68-88 determinants of GP and rat MBPs, and that both MBPs appear to be equally capable of stimulating these clones in vitro. However, the differences in the clonotype composition of the populations induced by immunization with these two antigens suggest that rat and GP MBPs are subject to different immunoregulatory constraints in the animal and may account for the difference in the encephalitogenic potential of these two antigens.

Animals↗
PubMed1988

The autoreactive T cell population in experimental allergic encephalomyelitis: T cell receptor beta-chain rearrangements.

T cell receptor beta-chain gene rearrangements were examined in myelin basic protein (MBP)-reactive T cell lines and hybridomas from Lewis (Lew) rats. Nearly 75% of the cloned hybrids were specific for the major encephalitogenic determinant residues 68-88 of guinea pig (GP) MBP; three fine specificities could be distinguished. Southern blot analysis of receptor beta-chain genes revealed polyclonality and shared rearrangements not seen in non-68-88-specific clones. Generation of short-term, encephalitogenic Lew T cell lines revealed rearrangements shared with the 68-88-specific hybrids, indicating that the hybrids were representative of the whole antigen-specific population and suggesting restricted V beta gene usage within this polyclonal population.

Animals↗
PubMed1988

A simple technique to distinguish rat from mouse chromosomes in T cell hybridomas.

Antigen-specific rat mouse T-cell hybridomas, prepared by fusing the BW5147 AKR thynoma with helper T cells from rats immunized with chicken ovalbumin, express both the rat and mouse major histocompatibility complex gene products. Using these functionally defined T-cell hybridomas, we have devised a technique based on the differential staining of the heterochromatin region of the rat and mouse chromosomes to distinguish the species of origin of the chromosomes. This technique should prove useful for screening potential hybrid cell lines and should aid in differentiating mouse from rat chromosomes for gene mapping studies.

Animals↗
PubMed1987

A synthetic peptide induces long-term protection from lethal infection with herpes simplex virus 2.

Immunization against viral pathogens is generally directed toward the induction of virus neutralizing antibody (VNA) and the maintenance of the potential for a second-set (IgG) response. Indeed, an elevated level of specific antibody is considered a reliable clinical indicator that a state of immunity exists in the host. However, in the case of herpes simplex virus (HSV), the presence of circulating VNA does not necessarily correlate with protection. Thus, it has been found that secondary infections occur in individuals even with high neutralizing titers to HSV, suggesting that antibody to the virus may be useless or even deleterious. In consideration of these facts, we were interested in inducing a T cell response to HSV. We had already shown that synthetic peptides corresponding to the NH3-terminal region of the glycoprotein D (gD) molecule of HSV could induce a strong T cell response when injected into mice, but did not, by themselves, confer protection. In this report, we examined the ability of peptides, covalently coupled to palmitic acid and incorporated into liposomes, to induce virus-specific T cell responses that confer protection against a lethal challenge of HSV-2. We have demonstrated that long-term protective immunity is achieved with a single immunization in the absence of neutralizing antibody when antigen is presented in this form. Furthermore, T cells but not serum from such immune mice can adoptively transfer this protection.

Acylation↗
PubMed1987

Induction of protective immunity against rabies by immunization with rabies virus ribonucleoprotein.

We have studied the ability of rabies virus ribonucleoprotein (RNP) to induce a protective immune response in animals against lethal challenge with rabies and rabies-related lyssa viruses. Liposomes containing either RNP or the glycoprotein (G protein) of a variant virus with multiple alterations in the G antigenic structure conferred no or poor protection, respectively, against lethal intracerebral challenge with rabies virus. By contrast, liposomes containing RNP and the variant G protein induced a good protective response, comparable to that achieved with inactivated virus vaccine against intracerebral challenge. Moreover, mice or raccoons immunized with RNP alone resisted lethal peripheral challenge with homologous or heterologous virus strains. These results indicate that the RNP of rabies virus plays a crucial role in induction of protective immunity.

Animals↗
PubMed1985

Tissue-specific, inducible and functional expression of the E alpha d MHC class II gene in transgenic mice.

We have introduced the class II E alpha d gene into (C57BL/6 X SJL) F2 mice which do not express their endogenous E alpha gene. The mRNA expression of the E alpha d gene shows the same tissue distribution as the endogenous class II genes except in the case of one mouse, which carried 19 copies of the E alpha d gene. In this mouse expression of E alpha d mRNA was seen in all tissues tested. Expression of the transgene was induced by gamma-interferon in isolated macrophages from the transgenic mice. In addition, fluorescence activated cell sorter (FACS) analysis, mixed lymphocyte response and antigen-presentation experiments showed that the product of the transferred gene is expressed on the cell surface and functions as a major histocompatibility complex restriction element. Transmission of the gene occurred only with female transgenic mice, all males were infertile or did not transmit the gene, suggesting an effect of the transferred DNA sequence on male reproductive function.

Animals↗
PubMed1985

Rearrangement and transcription of a T-cell receptor beta-chain gene in different T-cell subsets.

The functionally defined sets of T lymphocytes--helper T cells, cytotoxic T cells, and suppressor T cells--were examined for the possible involvement of a recently identified T-cell receptor beta gene locus in receptor formation. Since gene rearrangements are required for functional gene expression, cloned T-cell lines from each of the groups were surveyed for the expression of unique gene rearrangements. In addition, cell lines that showed gene rearrangements were further tested for the expression of the mature 1.2- to 1.3-kilobase mRNA transcribed from a productive gene rearrangement. The results of such experiments show that helper and cytotoxic T cells may use a common beta chain of the receptor, whereas suppressor cells do so rarely, if at all.

Animals↗
PubMed1985

The T cell response to the glycoprotein D of the herpes simplex virus: the significance of antigen conformation.

Synthetic peptides corresponding to the first 23 amino acids of the glycoprotein D molecule of herpes simplex virus have been used to immunize mice and examine the role of antigen conformation in T cell responses. The structure of the peptides was determined by circular dichroism studies and was shown to be consistent with theoretical structure predictions. T cell clones were found that could respond to peptides that were nonhelical, and this response, which was directed to the C-terminal determinant (residues 8-23), could be modified by a constrained N-terminal sequence (residues 1-7) of the peptide. Namely, substitution of Ala for Pro at position 7 induced an alpha-helix and inhibited the response. Furthermore, a response to the N-terminal part of the molecule seemed to be directed to the alpha-helix and correlated positively with calculated degree of helicity. This response was also modified, in this case, by the C-terminal part of the molecule. These results suggest that local secondary structure of an antigen may regulate T cell responses and that structural changes in the peptide antigen downstream from the determinant modify recognition of that determinant. Furthermore, antigen processing by the macrophage and antigen presentation of T cells appears to conserve antigen structural integrity.

Amino Acid Sequence↗