PubMed Health⌕ Search

Biomedical subjects

G Benichou

Publications and source records attributed to G Benichou.

At least 19 recordsLinked to original sources
PubMed2005

Effects of noninherited maternal antigens on allotransplant rejection in a transgenic mouse model.

We studied the influence of noninherited maternal antigen (NIMA) on allotransplant rejection using a mouse transgenic model. CBK transgenic (CBA [H-2k] expressing K(b) MHC class I transgene) mice were used as donors in heart transplantation experiments. Offspring of BM3.3 (CBA anti-K(b) TCR transgenic) male mice and (CBA x CBK)F1 females were used as NIMA (offspring that did not inherit K(b)) and IMA (offspring that inherited K(b) maternal antigen) recipient mice. Survival of allografts was monitored and the alloimmune response evaluated using an ELISPOT assay. IMA mice accepted CBK heart allografts and displayed no alloresponse to K(b+) cells. In contrast, mice never exposed to K(b) (offspring of BM3.3 males and CBA females) acutely rejected their grafts within 18 days posttransplantation and exhibited potent inflammatory alloresponses to K(b+) cells. NIMA mice displayed prolonged survival of allotransplants (MST >60 days). Although no deletion of anti-K(b) TCR transgenic cells was detected in these mice, they had a marked reduction in the frequency of activated alloreactive T cells producing type 1 (IFN-gamma and IL-2) cytokines and concomitant expansion of type 2 (IL-4) cytokine-secreting cells. Finally, depletion of CD4+ T cells from NIMA mice restored acute rejection of CBK hearts. This study is the first demonstration of the tolerogenic effects of NIMA on alloimmunity and allotransplant rejection in a transgenic model. It is shown that, although the NIMA tolerogenic effect is not due to deletion of alloreactive T cells, it is mediated by CD4+ T cells producing type 2 cytokines.

Animal Nutritional Physiological Phenomena↗
PubMed2001

Role of CD4+ and CD8+ T cells in allorecognition: lessons from corneal transplantation.

Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-gamma-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.

Animals↗
PubMed2001

CD28-independent costimulation of T cells in alloimmune responses.

T cell costimulation by B7 molecules plays an important role in the regulation of alloimmune responses. Although both B7-1 and B7-2 bind CD28 and CTLA-4 on T cells, the role of B7-1 and B7-2 signaling through CTLA-4 in regulating alloimmune responses is incompletely understood. To address this question, we transplanted CD28-deficient mice with fully allogeneic vascularized cardiac allografts and studied the effect of selective blockade of B7-1 or B7-2. These mice reject their grafts by a mechanism that involves both CD4(+) and CD8(+) T cells. Blockade of CTLA-4 or B7-1 significantly accelerated graft rejection. In contrast, B7-2 blockade significantly prolonged allograft survival and, unexpectedly, reversed the acceleration of graft rejection caused by CTLA-4 blockade. Furthermore, B7-2 blockade prolonged graft survival in recipients that were both CD28 and CTLA-4 deficient. Our data indicate that B7-1 is the dominant ligand for CTLA-4-mediated down-regulation of alloimmune responses in vivo and suggest that B7-2 has an additional receptor other than CD28 and CTLA-4 to provide a positive costimulatory signal for T cells.

Abatacept↗
PubMed2001

Antigenicity and immunogenicity of allogeneic retinal transplants.

The transplantation of neuronal cells and tissues represents a promising approach for the treatment of incurable neurodegenerative diseases. Indeed, it has been reported recently that retinal transplantation can rescue photoreceptor cells and delay age-related changes in various retinal layers in rodents. However, retinal grafts deteriorate progressively after placement in recipients' eyes. Here we investigated whether a host's immune response elicited toward the graft contributes to its deterioration. Using an ELISA spot assay, we measured T cell responses to retinal tissues placed in the vitreous cavity of syngeneic and allogeneic mice. We found that allogeneic retinas induced potent alloimmune responses mediated by T cells secreting type 1 cytokines (IFN-gamma and IL-2). No response was found in mice engrafted with syngeneic retinas. In addition, all syngeneic retinal grafts displayed no signs of tissue damage (at 55 days), while the majority of allogeneic retinas deteriorated as early as 12 days after placement. Next, we showed that anti-donor responses occurred within two phenotypically and functionally distinct T cell subsets: CD4+ T cells secreting IL-2 and CD8+ T cells producing IFN-gamma. Importantly, CD4+ T cells were necessary and sufficient to cause graft deterioration, while CD8+ T cells did not contribute to this process.

Animals↗
PubMed2001

Blockade of CD40-CD154 costimulatory pathway promotes survival of allogeneic corneal transplants.

PURPOSE: To determine the effect of systemic anti-CD154 monoclonal antibody on the survival of orthotopic murine corneal transplants. METHODS: BALB/c mice were used as recipients of syngeneic, multiple minor histocompatability (H)-disparate, or major histocompatibility complex MHC-mismatched corneal transplants. Recipient beds were either avascular (normal risk) or neovascularized (high risk). Mice were randomized to receive either anti-CD154 antibody or control immunoglobulin by intraperitoneal injection at surgery and once weekly after surgery. After orthotopic corneal transplantation, all grafts were evaluated for signs of rejection by slit lamp biomicroscopy over 8 weeks. The high-risk transplants were continuously observed until week 18 after the therapy was discontinued at week 8. Allospecific delayed-type hypersensitivity (DTH) was evaluated after transplantation in high-risk graft recipients. Frequency of interferon (IFN)-gamma-secreting T cells in the hosts was measured by enzyme-linked immunospot (ELISPOT) assay. RESULTS: In normal-risk transplantation, the 8-week survival rate improved from 25% in control mice to 88% in anti-CD154-treated hosts of minor H-disparate grafts (P = 0.0087) and from 78% in control mice to 100% in anti-CD154-treated recipients of MHC-mismatched transplants (P = 0.177). Of particular significance, in high-risk transplantation, anti-CD154 therapy dramatically enhanced the survival of both minor H- and MHC-disparate corneal transplants to 100% (P = 0.0001) and 92% (P = 0.0002), respectively. In addition, the anti-CD154-treated mice did not exhibit allospecific immunity. However, termination of anti-CD154 led to some loss in graft survival, especially among high-risk minor H-disparate grafts. The frequency of IFN-gamma-producing T cells was significantly reduced in anti-CD154-treated hosts. CONCLUSIONS: Continuous suppression of the CD40-CD154 costimulatory pathway promotes the acceptance of corneal transplants, regardless of the degree of allodisparity or preoperative risk. The beneficial effect of anti-CD154 treatment may be due in part to inhibition of Th1-mediated responses.

Animals↗
PubMed2000

CD4+ T cell responses to self- and mutated p53 determinants during tumorigenesis in mice.

We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells.

Amino Acid Sequence↗
PubMed2000

Induction of T-cell response to cryptic MHC determinants during allograft rejection.

The presentation of MHC peptides by recipient and donor antigen presenting cells is an essential element in allorecognition and allograft rejection. MHC proteins contains two sets of determinants: the dominant determinants that are efficiently processed and presented to T cells, and the cryptic determinants that are not presented sufficiently enough to induce T-cell responses in vivo. In transplanted mice, initial T-cell response to MHC peptides is consistently limited to a single or a few immunodominant determinants on donor MHC molecule. However, in this article we show that under appropriate circumstances the hierarchy of determinants on MHC molecules can be disrupted. First, we observed that gamma IFN can trigger de novo presentation of cryptic self-MHC peptides by spleen cells. Moreover, we showed that allotransplantation is associated with induction of T-cell responses to formerly cryptic determinants on both syngeneic and allogeneic MHC molecules. Our results suggest that cross-reactivity and inflammation are responsible for the initiation of these auto- and alloimmune responses after transplantation.

Amino Acid Sequence↗
PubMed2000

The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.

We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.

Animals↗
PubMed1999

De novo autoimmunity to cardiac myosin after heart transplantation and its contribution to the rejection process.

Allograft rejection is initiated by an immune response to donor MHC proteins. We recently reported that this response can result in breakdown of immune tolerance to a recipient self Ag. However, the contribution of this autoimmune response to graft rejection has yet to be determined. Here, we found that after mouse allogeneic heart transplantation, de novo CD4+ T cell and B cell autoimmune response to cardiac myosin (CM), a major contractile protein of cardiac muscle, is elicited in recipients. Importantly, CM is the autoantigen that causes autoimmune myocarditis, a heart autoimmune disease whose histopathological features resemble those observed in rejected cardiac transplants. Furthermore, T cell responses directed to CM peptide myhcalpha 334-352, a known myocarditogenic determinant, were detected in heart-transplanted mice. No responses to CM were observed in mice that had received an allogeneic skin graft or a syngeneic heart transplant, demonstrating that this response is tissue specific and that allogeneic response is necessary to break tolerance to CM. Next, we showed that sensitization of recipient mice with CM markedly accelerates the rejection of allogeneic heart. Therefore, posttransplant autoimmune response to CM is relevant to the rejection process. We conclude that transplantation-induced autoimmune response to CM represents a new mechanism that may play a significant role in cardiac transplant rejection.

Amino Acid Sequence↗
PubMed1999

Direct and indirect antigen recognition: the pathways to allograft immune rejection.

The immune rejection of allografts is mediated by T cells via two distinct pathways: the direct and the indirect pathways. Direct alloresponse to intact donor MHC molecules is ensured by T cells which are polyclonal and directed toward a variety of antigens. This response is highly sensitive to treatment by immunosuppressive drugs including Cyclosporin A. Indirect alloresponse is oligoclonal and involves a few dominant antigen peptides on donor MHC. In contrast to its direct counterpart, indirect allorecognition is thought to be poorly sensitive to blockade by cyclosporin A. It is likely that indirect and direct types of alloresponses play different roles in the physiology of the rejection process. T cell responses occurring via direct allorecognition play a critical role during the early phase of acute graft rejection by sensitizing the host to graft antigens. Alternatively, once such sensitization has taken place, indirect type of alloresponse may become predominant and presumably represent the driving force in the actual destruction of transplanted tissues. In addition, we and others have provided strong circumstantial evidence indicating that secondary T cell responses via indirect allorecognition spread to new determinants on donor MHC and tissue-specific antigens. This phenomenon is likely to play an important role in late and chronic rejection, a major obstacle to long-term graft acceptance in clinical transplantation. Finally, a series of studies have demonstrated that early, pre-transplant treatment with tolerogenic donor-derived MHC peptides can protect the graft from rejection in rodents. Although the mechanisms involved in MHC-peptide-induced tolerance are ill defined, this strategy represents a promising approach for ensuring long-lasting graft acceptance in the absence of widespread immunosuppression. It is now crucial to further explore the mechanims involved in immunogenicity and tolerogenicity of MHC peptides and to initiate clinical studies to evaluate the efficacy of blocking indirect alloresponses in transplanted patients.

Animals↗
PubMed1999

Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice.

The immune response to transplanted allogeneic tissues is mediated by T cells that recognize donor histocompatibility Ags either via direct (donor MHC and peptides) or indirect (recipient MHC and donor-derived peptides) allorecognition pathways. The relative contribution of each of these pathways to allograft rejection remains largely unknown. To address this, we used an enzyme-linked immunospot assay to define the frequency and cytokine phenotype of T cells responding via direct and indirect pathways to alloantigens at various time points following placement of allogeneic B10.A skin grafts on BALB/c recipient mice. During acute graft rejection >90% of the anti-B10.A T cell repertoire was directed toward intact donor MHC molecules, while T cells recognizing indirectly presented, donor-derived peptides accounted for <10%. This indirect response was comprised of reactivity toward both MHC-derived and, to a lesser extent, minor Ag-derived determinants. The direct and indirect alloresponses were predominantly detected in recipient lymph nodes and were mediated by T cells displaying a mixed type 1/type 2 cytokine phenotype. Six weeks following rejection, however, the memory allospecific T cell response became predominant in the recipient spleen, with only minimal activity detectable in the draining lymph nodes. This work provides a new approach for analysis of the immunophysiology of allograft rejection and should be useful for monitoring immune responses to graft Ags in human transplant recipients.

Animals↗
PubMed1999

T cell repertoire in mice with alopecia areata.

It has become clear that skin infiltrating autoreactive CD4+ T helper cells play a crucial role in the initiation of alopecia areata. However, the natures of the pathogenic T cell clones as well as of the skin antigen they recognize remain obscure. Here, we analyzed the T cell receptor repertoire expressed in the spleen of diseased mice. We consistently observed the dominant expansion of a limited set of T cell clones expressing Vbeta8.2/Jbeta2.5 T cell receptor rearrangement. We conclude that T cell response in mice alopecia areata is markedly oligoclonal; a feature that may permit the design of selective immunotherapy.

Alopecia Areata↗
PubMed1998

Differential activation of T cells by natural antigen peptide analogues: influence on autoimmune and alloimmune in vivo T cell responses.

Recent studies using synthetic altered peptide ligands (Analogues) have led to the fine dissection of TCR-mediated T cell functions elicited by Ag recognition. Certain Analogues behave as full agonists of the antigenic peptide while others are partial agonists in that they only trigger selected T cell functions. Additionally, peptide Analogues can behave as antagonists by inhibiting functions of T cell clones when coincubated with the wild-type peptide. In fetal thymic organ cultures, synthetic altered peptide ligands can impact T cell repertoire selection. However, the influence of naturally occurring peptide Analogues on T cell immunity in vivo remains hypothetical. We previously reported that, in B10.A mice, immunogenicity and tolerogenicity of the self-MHC class I peptide, Ld 61-80, were influenced by the presentation of a cross-reactive self-peptide, Kk 61-80. Here, we show that Kk 61-80 self-peptide represents a partial agonist of Ld 61-80 in that it induced the proliferation but not the lymphokine production of Ld 61-80-primed T cells. Next, we showed that presentation of Kk 61-80 Analogue peptide mediated T cell tolerance toward Ld 61-80 self-peptide. Alternatively, when Ld protein represented an alloantigen displayed on transplanted cells, immunization with Kk 61-80 Analogue sensitized recipient mice to Ld 61-80 peptide, thus inducing potent immune responses to donor cells. These results show that the presentation of natural Analogue peptides may represent an essential component of T cell responses involved in autoimmunity and transplant rejection.

Amino Acid Sequence↗
PubMed1998

The presentation of self and allogeneic MHC peptides to T lymphocytes.

The presentation of donor-derived MHC peptides by recipient APCs to T cells is an essential component of the rejection of allografts (indirect allorecognition). Initial alloreactive T cell response is confined to a few well processed and presented dominant determinants on donor MHC. However, during long-term graft rejection, T cell response spreads to formerly poorly presented cryptic allogeneic MHC peptides. This phenomenon is likely to play an important role in the amplification and the perpetuation of the rejection process. Additionally, we present evidence that T cell repertoire selection to allogeneic MHC peptides is acquired via recognition of self-MHC peptides presented in the thymus during ontogeny. Supporting this view, we have shown that indirect alloresponses can lead to self-T cell tolerance breakdown to cross-reactive determinants on self-MHC molecules or alternatively that sensitization of recipients to self-MHC peptides can lead to accelerated graft rejection. It is therefore essential to determine the factors which govern the processing and presentation of self and allogeneic MHC molecules and to elucidate the mechanisms regulating subsequent T cell responses in order to design antigen-specific based immune therapies in transplantation.

Antigen Presentation↗
PubMed1997

Induction of T helper 2 immunity to an immunodominant allopeptide.

Neonatal tolerance to alloantigens and autoantigens in mice is mediated by T helper (Th)2 immunity. If a strong and pure Th2 response could be engaged to alloantigens in adult mice, it might result in allograft tolerance. In an attempt to induce Th2 immunity in adults, we studied the T-cell response to peptide I-A beta(k)58-71 (I-Ap), a dominant indirect pathway determinant during rejection of B10.A skin by BALB/c mice. Our data show that the naturally occurring response to this peptide during rejection is Th1, consistent with the notion that Th1 immunity is central to destruction of the allograft. In contrast, vigorous and unipolar Th2-type immunity to this peptide can be readily induced by intraperitoneal immunization with incomplete Freund's adjuvant, a protocol previously thought to induce T-cell unresponsiveness. Thus, adjuvant can be used to Th2-guide the indirect pathway alloresponse in an effort to antagonize naturally occurring Th1 alloimmunity.

Animals↗
PubMed1997

Prevention and suppression of autoimmune encephalomyelitis by EUK-8, a synthetic catalytic scavenger of oxygen-reactive metabolites.

Breakdown of T cell tolerance to self-myelin basic protein induces an autoimmune process that leads to demyelination of the central nervous system (CNS) in multiple sclerosis (MS) patients. While the autoimmune disease is initiated by antigen-specific autoreactive T cells, there is accumulating evidence that CNS injury is essentially mediated by CNS-infiltrating inflammatory cells. In addition, it is established that activated macrophages and polymorphonuclear cells contribute to tissue damage in several inflammatory diseases by releasing highly reactive oxygen metabolites. It was therefore possible that demyelination associated with MS results from oxidative injury caused by a cascade of oxygen reactive metabolites produced by CNS-infiltrating activated macrophages and other inflammatory cells. To address this question, we tested the effect of a synthetic catalytic scavenger of oxygen radicals, EUK-8, on experimental allergic encephalomyelitis (EAE) in mice, the animal model for MS in humans. We observed that repeated injection of EUK-8 starting at the time of EAE induction delayed the onset and markedly reduced the severity of the disease. Strikingly, all EUK-8-treated mice completely recovered after 40 days. In addition, we showed that posttreatment with EUK-8 4 days after EAE induction also resulted in a significant amelioration of EAE disease. These results indicate that oxygen metabolites secreted by inflammatory cells at the site of tissue destruction play a major role in the induction and presumably the perpetuation of the autoimmune disease. This study also suggests that treatment with oxygen metabolites scavengers may represent a novel and promising strategy to prevent the onset and to block the course of ongoing autoimmune encephalomyelitis and other inflammatory autoimmune diseases.

Animals↗