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H Offner

Publications and source records attributed to H Offner.

At least 73 records · Page 4Linked to original sources
PubMed1995

Effects of anti-CD4 antibody: enhancement of lymph node PPD-memory T cell response.

In vitro incubations of CD4+ T cells with anti-CD4 monoclonal antibody (Mab) demonstrated saturation binding and inhibited both PPD-stimulated proliferation and delayed-type hypersensitivity (DTH) after passive transfer of these cells into naive rats. In comparison, in vivo administration of anti-CD4 Mab into rats, 2 weeks after CFA immunization (PPD priming), saturated CD4 molecules expressed on T lymphocytes and depleted significant percentages of CD4+ T cells from blood, spleen, and lymph nodes, yet failed to cause significant inhibition of PPD-stimulated DTH ear swelling. Only repeated in vivo administration of anti-CD4 Mabs during the CFA/PPD antigen priming caused significant decreases (36 +/- 5%) in PPD-stimulated DTH ear swelling. T cells isolated from the blood and spleen showed insignificant relative decreases in PPD-stimulated proliferation after anti-CD4 treatments. In contrast, PPD-stimulated proliferation of T cells isolated from the draining lymph nodes after anti-CD4 treatments showed dramatic increases in PPD reactivity. PPD stimulation of T cells isolated from the draining lymph nodes of anti-CD4 Mab-treated rats produced relative phenotypic changes in CD4 coexpressions with CD45RC (inverse memory), CD49d (inflammatory adhesion integrin VLA-4), and OX40 (CD4+ blast), representative of memory CD4+ T cell blasts with reduced capacity for endothelial infiltration. These data demonstrate that depletion of CD4+ T cells by anti-CD4 Mab injections, administered either during or after antigen priming, selectively enhanced memory responses in T lymphocytes in the draining lymph nodes.

Animals↗
PubMed1995

T cells with encephalitogenic potential from multiple sclerosis patients and Lewis rats fail to induce disease in SCID mice following intracisternal injection.

Intracisternal (IC) transfer of cerebrospinal fluid (CSF) mononuclear cells from multiple sclerosis (MS) patients has been reported by others to induce an 'MS-like pathology' in severe combined immunodeficient (SCID) mice. We injected cells from several sources intracisternally into SCID mice and assessed the recipients for clinical and histological disease. CSF cells and myelin basic protein (BP)-specific T lymphocytes from MS patients failed to induce clinical or histological disease following IC injection in SCID mice. Similarly, encephalitogenic BP-specific T cells from Lewis rats were unable to induce disease after IC injection in either SCID mice or Lewis rats, even at cell numbers which induced experimental autoimmune encephalomyelitis in Lewis rats following intraperitoneal (IP) injection. In contrast, naive Lewis rat splenocytes, which were capable of inducing lethal graft-versus-host (GVH) disease following IP transfer in SCID mice, induced paralysis and histopathological changes following IC transfer in SCID mice. We conclude that MS CSF cells do not typically transfer disease into SCID mice following IC injection. Furthermore, it appears likely that neuropathological disease following IC transfer of cells reflects the potential of the transferred cells for inducing GVH disease. Specific recognition of neuroantigens by T cells, as occurs in EAE, is probably not involved in the transfer of paralytic disease by IC transferred MS patient CSF cells.

Animals↗
PubMed1995

Antigen-specific T-cell activations distinguished by in vivo anti-CD4 antibody treatment.

This study identifies activation characteristics of PPD-responsive T-cells that emerge after treatment with anti-CD4 monoclonal antibody (Mab). PPD-stimulated T-cell proliferations, OX40 phenotype and protein tyrosine phosphorylations involving p56lck (pp56lck) were compared to Con A stimulations using T-cells isolated from spleen and draining lymph node of CFA/PPD-immunized rats either untreated or treated in vivo with anti-CD4 Mab. Splenocytes stimulated by concanavalin A (Con A) showed correlated increases in proliferation, levels of pp56lck, and OX40 expression; these parameters were not correlated in splenocytes after PPD-stimulations. T-cells isolated from lymph nodes draining the site of CFA/PPD immunization proliferated in response to stimulation by either PPD or Con A, but only PPD-responsive cells showed correlation to the OX40 activation phenotype and increased levels of pp56lck. CD4+ T-cells isolated from either tissue compartment after anti-CD4 Mab treatments showed higher background and PPD-stimulated proliferations, and expressed lower levels of OX40. In contrast, anti-CD4 Mab treatments reduced (60%) and abolished Con A-stimulated proliferations of splenocytes and lymph node T-cells, respectively. The effects of anti-CD4 Mab treatment on pp56lck levels correlated only to the changes observed for Con A stimulations of splenocytes. These results demonstrate that PPD antigen-specific T-cell populations recovered from different tissue compartments were resistant to in vivo anti-CD4 Mab treatments and did not show the activation changes characteristics of CD4+ T-cells after Con A stimulation.

Animals↗
PubMed1994

Coculture of TCR peptide-specific T cells with basic protein-specific T cells inhibits proliferation, IL-3 mRNA, and transfer of experimental autoimmune encephalomyelitis.

TCR peptides, namely V beta 8.2-39-59 or the minimal idiotope, V beta 8-44-54, can treat experimental autoimmune encephalomyelitis (EAE) in Lewis rats, presumably by activating naturally induced TCR peptide-specific T cells that arise in response to the focused appearance of V beta 8.2+ encephalitogenic T cells. The purpose of the present study was to evaluate the mechanisms by which TCR peptides inhibit EAE. We found that treatment of EAE with the V beta 8.2-39-59 peptide did not induce any evidence of DNA fragmentation (apoptosis) in spinal cord cells isolated from clinically well rats, implicating a regulatory rather than a deletional mechanism. TCR peptide-specific T cell lines failed to inhibit EAE induced by already activated BP-specific T cells when the two T cell specificities were co-injected. However, coculturing the encephalitogenic T cells in the presence of the regulatory T cells during the activation step before transfer almost completely inhibited the induction of EAE. Inhibition could be induced by direct contact between the two cell types or by soluble factors produced in a transwell system, but was greatly enhanced when soluble V beta 8.2-39-59 peptide was used to optimally activate the regulatory T cells. The inhibition was regulatory cell dose dependent, and was reflected in vitro by reduced proliferation response and mRNA production for IL-3, and to a lesser extent, IFN-gamma and IL-2. These results indicate that regulation induced by TCR peptides involves cell-cell interactions that lead to the production and release of soluble factors that locally inhibit the activation of encephalitogenic T cells expressing MHC-bound idiotopes of the target V beta-chain, and possibly "bystander" specificities expressing different V beta-chains.

Amino Acid Sequence↗
PubMed1994

Definition of encephalitogenic and immunodominant epitopes of guinea pig myelin basic protein (Gp-BP) in Lewis rats tolerized neonatally with Gp-BP or Gp-BP peptides.

Two distinct epitopes of guinea pig basic protein (Gp-BP), residues 72-89 and 87-99, possess encephalitogenic activity in Lewis rats. The purpose of this study was to determine to what degree the 87-99 epitope functions in rats that have been injected with whole Gp-BP, and whether additional epitopes in Gp-BP are encephalitogenic. To address these questions, we induced neonatal tolerance to the dominant synthetic (S)72-89 peptide or to the combination of both S72-89 and S87-99 peptides, and evaluated resistance to experimental autoimmune encephalomyelitis (EAE) induced by Gp-BP, as well as T cell responses to peptides that encompassed most of the Gp-BP molecule. The results demonstrated that virtually all of the encephalitogenic activity of Gp-BP resides within the two described encephalitogenic epitopes. Moreover, deletion of responses to the dominant epitopes prompted T cell responses to other nonencephalitogenic epitopes of Gp-BP, a pattern of response observed previously in rats that had recovered from EAE and in those protected from EAE by vaccination with TCR peptides. These data may have relevance to human autoimmune diseases such as multiple sclerosis in that naturally or immunologically regulated responses to dominant epitopes that are likely to be encephalitogenic may be obscured by increased responses to relatively innocuous determinants of basic protein. Elevated responses to potentially pathogenic autoantigens will likely involve both types of determinants, thus, underscoring the importance of distinguishing encephalitogenic from nonencephalitogenic determinants.

Amino Acid Sequence↗
PubMed1994

Analysis of V beta 8-CDR3 sequences derived from central nervous system of Lewis rats with experimental autoimmune encephalomyelitis.

We have recently demonstrated that a strong bias for expression of V beta 8.2 is manifested early during the onset of experimental autoimmune encephalomyelitis (EAE) induced by guinea pig basic protein (Gp-BP) immunization of Lewis rats. More importantly, the V beta 8.2 bias was observed in T cells infiltrating the spinal cord (SC) and in cerebrospinal fluid (CSF), but was not present in T cells isolated from the periphery. Here, we report the V beta 8-CDR3 sequences found in unselected SC, CSF, and lymph node (LN) T cell populations at onset of Gp-BP-induced EAE. Striking similarities were observed among sequences derived from SC and CSF. Evidence for oligoclonal expansion of V beta 8.2 sequences associated with previously characterized encephalitogenic clones was observed in both SC and CSF, but not in LN. An AspSer CDR3 motif identified in encephalitogenic clones recognizing the dominant 72-89 epitope of Gp-BP was found in 9/22 SC cDNA clones, 11/24 CSF cDNA clones, and 1/16 LN cDNA clones. Interestingly, J beta 2.7 and J beta 1.3 were also highly represented in SC and CSF, but not in LN. Given that these sequences were derived from T cells present at the site of autoimmune attack and not selected by in vitro manipulation, the data offer compelling evidence that 1) selective recruitment and/or expansion of V beta 8.2+ T cells are occurring in the central nervous system; 2) these events are at least partially dependent on V beta residues which are likely to influence Ag binding; and 3) CSF-derived T cells provide a representative view of CNS events at the onset of EAE.

Amino Acid Sequence↗
PubMed1994

Immunity to T cell receptor peptides: theory and applications.

In this review, we describe an anti-idiotypic regulatory mechanism that is naturally induced by the autoimmune disease process, and that can be boosted by injection of TCR peptides that mimic epitopes generated naturally from germline sequences. The striking similarities in the induction and characteristics of rodent and human T cells specific for TCR peptides support the generality of the observation, and enhance the probability that this immunoregulatory mechanism will have application in human organ-specific autoimmune diseases that are characterized by oligoclonal expression of TCR V genes. The major challenges that remain to be resolved to make the TCR peptide therapy more widely applicable include (1) establishing disease-relevant V gene biases in individual patients, (2) identifying biologically active TCR peptide sequences, and (3) demonstrating that the induction of anti-TCR peptide immunity in humans can reduce the pernicious activity of autoreactive T cells putatively directed at organ-specific target antigens.

Amino Acid Sequence↗
PubMed1994

Understanding the CD4 molecule: surface expression and function.

Surface expression of the CD4 glycoprotein molecule is postulated to facilitate antigen recognition through the T cell receptor (TCR) and is itself a receptor for human immunodeficiency virus (HIV)-gp120 glycoprotein. Both antigen-stimulated TCR activation and HIV infectivity can be blocked by whole anti-CD4 antibodies. Although selective modulation of CD4 from the surface by gangliosides (GM1) blocks HIV infectivity, it enhances associated TCR function. Enhanced TCR function has also been observed after intracellular delivery of synthetic CD4 mRNA-antisense oligodeoxynucleotides (ODN) that block de novo synthesis of CD4. These specific CD4 modulations were mechanistically different from one another yet they both selectively removed the CD4 molecule from the T cell surface and enhanced antigen-stimulated function through the TCR. The proposed role of CD4 during TCR function and HIV infectivity was developed, in part, according to decreases following CD4 antagonism by whole antibody or down-modulation of CD4 by phorbol-stimulated protein kinase C activity. Selective CD4 modulations have independently redefined the specific contributions of CD4 surface expression during T cell activation and may establish a role for CD4 receptor subtypes during HIV-1 infection of CD4+ cells.

Animals↗
PubMed1994

Target organ-specific up-regulation of the MRC OX-40 marker and selective production of Th1 lymphokine mRNA by encephalitogenic T helper cells isolated from the spinal cord of rats with experimental autoimmune encephalomyelitis.

Lewis x Buffalo F1 rat lymphocytes express both forms of the allelic marker RT7.1 (Lewis) and RT7.2 (Buffalo). We generated myelin basic protein (MBP)-specific encephalitogenic F1 T helper cell lines and adoptively transferred them into naive irradiated Lewis recipients, which enabled us to detect and isolate donor T cells (with RT7.2) within the recipients. The spinal cord and cerebrospinal fluid (CSF) were highly enriched for the donor T cells compared with the blood and spleen. The donor cell number peaked on the first day of disease in the spinal cord and CSF and decreased as the disease progressed. A high percentage of the donor T cells isolated from the spinal cord were positive for the T helper cell activation marker OX-40, whereas a (lower) percentage of CSF donor cells expressed OX-40. Donor cells isolated from blood or spleen were negative for OX-40 expression. In contrast, the IL-2 receptor (CD25) was positive on all the transferred T cells in all tissue sites examined. Cell-sorting experiments showed that the MBP-specific donor cells were enriched for IFN-gamma, IL-2, TNF-alpha, and IL-3 mRNA when compared with the host-recruited spinal cord cells, whereas similar amounts of IL-10 mRNA were produced by both populations. Lymphokine mRNA production was also enriched in donor T cells isolated from the spinal cord compared with donor T cells isolated from the spleen. The spinal cord donor cells produced higher levels of IL-2, IFN-gamma, and IL-3 mRNA, whereas similar amounts of IL-10 and TNF-alpha mRNA were produced from donor cells isolated from the spleen and the spinal cord. Our data suggest that the amount/percentage, activation state, and enhanced lymphokine production at the site of inflammation are all important factors in determining the autoimmune potential of Ag-specific effector T helper cells.

Animals↗
PubMed1994

Immunity to TCR peptides in multiple sclerosis. I. Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides.

Immunization with disease-associated TCR V region peptides is an effective treatment for experimental autoimmune encephalomyelitis. Myelin basic protein-specific T cells, which induce experimental autoimmune encephalomyelitis in many animal strains, may be important in the pathogenesis of multiple sclerosis. Myelin basic protein-specific T cell clones from some multiple sclerosis patients preferentially use TCR V genes from the V beta 5.2 and V beta 6.1 families. To assess the safety and immunogenicity of TCR V beta 5.2 and V beta 6.1 peptides, we injected 11 multiple sclerosis patients with varying doses of two synthetic peptides, TCR V beta 5.2(39-59) and V beta 6.1(39-59), encompassing the CDR2 region of these V gene families. Low doses (100 to 300 micrograms) of peptide induced T cell immunity in 7 of 11 patients to one or both peptides. Delayed type hypersensitivity skin responses to the peptides were observed in three of seven responders, and TCR peptide-specific Ab occurred in two of seven T cell responders. Low doses of TCR peptides produced no side effects and did not cause broad spectrum immunosuppression. Synthetic TCR V region peptides can induce T cell immunity safely in humans and may prove useful in treating human autoimmune diseases.

Adult↗
PubMed1994

Immunity to TCR peptides in multiple sclerosis. II. T cell recognition of V beta 5.2 and V beta 6.1 CDR2 peptides.

The biased expression of V beta 5.2 and V beta 6.1 by T cells specific for myelin basic protein (BP) has led to our use of TCR peptides from these V gene sequences to induce anti-TCR immunity in patients with multiple sclerosis (MS). Injection of V beta 5.2-39-59 or V beta 6.1-39-59 peptides significantly increased the peptide specific T cell frequency in 7 of 11 MS patients, often with an accompanying delayed hypersensitivity reaction at the injection site. Here, we validate these cellular immune responses by characterizing TCR peptide specific T cells from an MS patient with biased V beta 5.2 expression in BP reactive T cells before treatment with TCR peptides, and from two MS patients in whom the frequencies of anti-TCR peptide specific T cells were significantly boosted after injection with low doses of TCR peptides. In both cases, T cell lines were established with relative ease, especially after boosting with the peptides. A V beta 5.2-39-59 reactive line responded selectively to the boosting peptide and was restricted by both MHC class I (HLA-B7) and MHC class II (HLA-DR2) molecules. Characterization of 22 clonal isolates revealed that the responding T cells were predominantly activated CD4+CD8lo, circulating memory cells restricted by either HLA-B7 or HLA-DR2, that utilized mainly V beta 4, V beta 6, V beta 12, and V beta 14, but not V beta 5.2 in their TCR. T cell isolates specific for V beta 6.1-39-59 possessed similar characteristics but contained specificities cross-reactive with an N-terminal sequence on V beta 5.2-39-59. Upon stimulation with peptide or Con A, the TCR peptide specific T cell lines had increased message production for IFN-gamma, GM-CSF, IL-4, IL-5, and to a lesser degree, IL-2. This lymphokine mRNA profile differed from a BP-specific T cell line that produced message for IFN-gamma and GM-CSF but low or absent levels of IL-4 and IL-5. The extensive parallels between human T cells specific for V beta 5.2 and V beta 6.1 CDR2 peptides and rat T cells specific for V beta 8.2 CDR2 peptide that are highly protective against experimental encephalomyelitis strengthen the rationale for the therapeutic use of TCR peptides in human autoimmunity.

Adult↗
PubMed1994

Enhanced T-helper cell function following CD4 modulation.

T cells made CD4- by ganglioside (GM1) treatment were cultured in antisense oligodeoxynucleotides complementary to mRNA for CD4. Antisense treatments decreased CD4 levels by 45% but did not prolong the total CD4 modulation by GM1 pretreatment. Northern blot analysis demonstrated that CD4 message production did not change after ganglioside modulation and consequently that it was different from antisense CD4 modulation. However, modulation of CD4 from the cell surface by either GM1 or antisense resulted in greater proliferation and enhanced DTH when challenged with recall antigen. These results demonstrate that selective decrease of CD4 increased antigen-specific T cell responses.

Animals↗
PubMed1994

Human myelin basic protein (MBP) epitopes recognized by mouse MBP-selected T cell lines from multiple sclerosis patients.

We investigated whether myelin basic protein (MBP)-reactive T cells from multiple sclerosis (MS) patients can recognize mouse MBP since this is an expected requirement for the transfer of experimental autoimmune encephalomyelitis (EAE) into severe combined immunodeficiency (SCID) mouse-human chimeras. Peripheral blood mononuclear cells from 11 MS patients were analyzed for in vitro proliferation to mouse MBP. Six patients (55%) responded to mouse MBP at the first or second stimulation. Five T cell lines, selected with mouse MBP from five MS patients, were analyzed for their proliferation to mouse and human MBP and to a panel of synthetic peptides of human MBP. Four of the five lines recognized mouse MBP. In vitro proliferation was restricted by MHC class II in one line tested for MHC restriction. One of the five lines recognized whole human MBP and all five of the lines responded to at least one of the five synthetic peptides corresponding to human MBP residues 8-28, 67-90, 84-102, 87-99 or 130-149. These results show that MS patient T cells recognize mouse MBP and suggest that distinct human MBP epitopes are immunologically cross-reactive with epitopes of mouse MBP.

Amino Acid Sequence↗
PubMed1994

The effect of TCR V beta 8 peptide protection and therapy on T cell populations isolated from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis.

Vaccination or treatment of Lewis rats with TCR V beta 8 peptides can prevent or reverse the clinical signs of experimental autoimmune encephalomyelitis (EAE) which is mediated predominantly by V beta 8.2+ CD4+/CD45R lo T cells. However, rats protected or treated with V beta 8 peptides still developed histological lesions in the spinal cord (SC), even though they remained clinically well. We sought to discern phenotypic changes characteristic of these SC infiltrating lymphocytes. In particular, we focused on whether the immunoregulatory mechanism induced by TCR peptides caused a reduction of V beta 8.2+ T cells, or induced changes in CD45R lo or hi/CD4+ subpopulations that have been associated respectively with EAE induction or recovery. In the V beta 8 peptide vaccinated rats there was a dramatic decrease in the number of V beta 8.2+ T cells isolated from the SC early in disease. During the recovery phase, however, the number of V beta 8.2+ SC T cells was similar in protected and control groups; in contrast, there was striking reduction in the number and size of CD45R hi/CD4+ T cells in the protected animals. In rats treated with V beta 8.2 peptide, no changes were observed in the number of SC V beta 8.2+ T cells or expression of V beta 8.2 message, but similar to vaccinated rats, there was a marked decrease in the number of CD45R hi/CD4+ T cells. These data suggest that vaccination with TCR peptides prevented the initial influx of encephalitogenic V beta 8.2+ T cells into the central nervous system (CNS), whereas treatment appeared to inactivate V beta 8.2+ T cells already present in the CNS. In both cases, TCR peptide-induced inhibition of the encephalitogenic T cells apparently preempted the need for CD45R hi/CD4+ T cells that may normally be necessary to resolve the disease.

Amino Acid Sequence↗
PubMed1993

Where, when, and how to detect biased expression of disease-relevant V beta genes in rats with experimental autoimmune encephalomyelitis.

The biased use of V beta 8.2 and V beta 6 in rats by encephalitogenic T cells specific for the S72-89 and S87-99 epitopes of guinea pig basic protein (Gp-BP) has allowed the use of anti-V beta antibodies and synthetic TCR peptides for treatment of experimental autoimmune encephalomyelitis (EAE). Striking V gene biases also occur in human autoimmune diseases, raising the question of to what degree these biases reflect potentially pathogenic T cells. To address this question, we evaluated the expression of the EAE-associated marker V beta 8.2 and V beta 6 molecules in the periphery, spinal cord (SC), and cerebrospinal fluid (CSF) during the course of EAE, in unselected, IL-2-expanded, and Gp-BP-restimulated populations. In CSF cells, there was a strong bias for the marker V beta before the onset of EAE, but this bias was not enhanced by IL-2, which skewed the CSF population to > 80% CD8+ T cells. In SC, the marker V beta were expressed optimally during the onset of EAE, even in unselected cells, and this bias could be enhanced sequentially by IL-2 expansion and Gp-BP restimulation. During the recovery phase, however, the marker V beta 8.2 bias was obfuscated by the appearance of a heterogeneous V beta T cell population. Biased expression of the marker V genes was not detected in unselected or IL-2-expanded peripheral cells at any time during EAE. These data suggest that peripheral T cells bearing the disease-relevant V genes first appeared in CSF before disease onset and then migrated to SC beginning on the first day of clinical signs. During the recovery phase of the disease, these cells were diluted by an influx of T cells bearing other V beta genes, requiring restimulation with Gp-BP to observe the V beta 8.2 bias. These data have important implications for the interpretation of V beta gene biases that have been reported in human autoimmune diseases.

Amino Acid Sequence↗
PubMed1993

Treatment of relapsing experimental autoimmune encephalomyelitis with T cell receptor peptides.

Restricted T cell receptor (TCR) VB gene usage by T cells for recognition of antigens involved in the production of experimental autoimmune encephalomyelitis (EAE) offers the possibility of selective immunotherapy. We determined the preferential VB gene usage of lymph node-derived clones from SJL/J mice to recognize the encephalitogenic epitope PLP 139-151 and from PL/J mice to recognize the newly described encephalitogenic epitope PLP 43-64. In addition, the VB gene usage for recognition of PLP 139-151 by T cell lines derived from SJL/J spinal cords was analyzed. Lymph node-derived SJL/J lines and clones specific for PLP 139-151 expressed VB2, VB4, and VB17a preferentially, and PL/J lines and clones specific for PLP 43-64 expressed VB2 and VB8.2 preferentially. A VB4 + SJL/J clone and a VB8.2 + PL/J clone were encephalitogenic. Encephalitogenic SJL/J lines derived from spinal cord expressed VB2, VB10, VB16, and VB17a preferentially, with a predominance of VB2. Candidate TCR peptides were synthesized and tested from the VB gene families VB4, VB8.2, and VB17a, based on our data and previous data on BP-induced EAE in mice. Treatment of relapsing EAE (R-EAE) in SJL/J mice with VB4 and VB17a peptides reduced clinical and histological disease severity, and treatment of R-EAE in (PLxSJL)F1 mice with VB4 and VB8.2 peptides also reduced clinical and histological disease. The use of TCR peptide therapy may have applications for the treatment of human autoimmune diseases such as multiple sclerosis.

Amino Acid Sequence↗