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J P Soulillou

Publications and source records attributed to J P Soulillou.

At least 19 recordsLinked to original sources
PubMed2006

Blood T-cell repertoire in idiopathic nephrotic syndrome recurrence following kidney transplantation.

Corticosteroid resistant idiopathic nephrotic syndrome (CR-INS) is a glomerulopathy that recurs after kidney transplantation in 30-50% of patients, suggesting the involvement of systemic albuminuric factors, probably produced by activated T cells. We investigated peripheral T-cell selection and expansion before and after transplantation to identify and characterize T-lymphocyte patterns potentially associated with INS recurrence. We used a combined qualitative and quantitative assessment of Vbeta mRNA alterations at the level of the complementary determining region 3-length distribution (CDR3-LD) of the T-cell receptor (TCR). Peripheral blood mononuclear cells (PBMC) were collected from 18 CR-INS patients (8 with recurrence and 10 without recurrence) on the day of transplantation as well as at 1 month, 1 year and 5 years after transplantation, and Vbeta transcriptomes were analyzed. Our data show that blood T cells from patients with INS recurrence display a TCR repertoire that is stable in time and has a similar level of CDR3-LD alterations as the T-cell repertoire of control patients, both before and after transplantation. These results suggest that the process of INS recurrence does not involve TCR activation or specific clonal expansion of T cells. However, these results do not exclude a role for T cells in the production of an albuminuric factor.

Adolescent↗
PubMed2002

Inhibition of graft arteriosclerosis development in rat aortas following heme oxygenase-1 gene transfer.

Heme oxygenase 1 (HO-1) is an enzyme which degrades heme into tree end products: biliverdin, free iron and carbon monoxide. This enzyme has recently been shown to have anti-inflammatory and tissue protective effects. HO-1 expression is involved in organ protection in pathological situations, and immunosuppressive treatments resulting in indefinite graft survival without chronic rejection have been associated with HO-1 expression by cells of the vessel wall. The aim of this study was to analyze the effect of specific HO-1 overexpression. We used a recombinant adenovirus coding for human HO-1 cDNA in a rat aorta chronic rejection model, 30 days after transplantation. Control groups included rats non treated or treated with a non-coding adenovirus Addl324. We first demonstrated that AdHO-1 was efficiently expressed in endothelial cells in vitro, and in rat aortas ex vivo after adenovirus gene transfer. We found that intimal thickening in AdHO-1 treated aortas (10.8 +/- 3.8%, n=5) was significantly decreased compared to untreated (21.2 +/- 5.6%, n = 5) or Addl324-treated (21.1 +/- 1.2%, n = 4) aortas. Immunohistology showed that treatment with AdHO-1 resulted in a significant reduction in leukocyte infiltration and a decreasing number of VSMC in the intima, compared to Addl324-treated aortas. However, this effect of HO-1 on chronic rejection did not imply modifications on numbers of apoptotic cells in the graft or of alloantibody levels. We have demonstrated, for the first time, that specific HO-1 overexpression following gene transfer of HO-1 inhibited chronic rejection by reducing leukocyte and VSMC infiltration of the aorta intima.

Adenoviridae↗
PubMed2001

Controlling the incidence of infection and malignancy by modifying immunosuppression.

Long-term outcomes in renal transplantation have improved over the years but are still a matter of concern. Because patients typically require lifelong immunosuppression, the risks of cancer and infection associated with immunosuppressive agents continue to demand attention. Physicians strive endlessly to find the right balance between the level of immunosuppression required to prevent rejection and the level that will minimize dose-dependent side effects. Data presented in this paper suggest that some renal transplant recipients might have more than necessary immunosuppression during maintenance therapy and that reducing the immunosuppressant dose can decrease cancer incidence, without worsening long-term patient or allograft survival. Additionally, data were examined suggesting that immunosuppressive agents might be associated with different risks for cancer, specifically, the potential advantage of reduced cancer risk for sirolimus and sirolimus derivatives in comparison with standard immunosuppressive agents. Although promising, these preliminary results are from preclinical studies, and further study is warranted.

Humans↗
PubMed2001

Direct recognition of foreign MHC determinants by naive T cells mobilizes specific Vbeta families without skewing of the complementarity-determining region 3 length distribution.

The capacity of T cells to interact with nonself-APC, also referred to as direct allorecognition, is an essential feature of the cellular response involved in graft rejection. However, there is no study on TCR repertoire biases associated with direct restricted T cell activation. In this paper, we have addressed the impact of direct recognition on the whole naive T cell repertoire, using a new approach that provides, for the first time, an integrated depiction of the quantitative and qualitative alterations in the TCR Vbeta transcriptome. This method can differentiate resting patterns from polyclonally activated ones, as evidenced by superantigen usage. According to this new readout, we show that direct recognition of nonself-MHC molecules triggers mRNA accumulation of several TCR Vbeta families, specific to the combination studied. Moreover, in marked contrast to the situation that prevails in indirect allorecognition, T cell activation through the direct presentation pathway was not associated with skewing of the complementarity determining region (CDR) 3 length distribution. Altogether, these data argue for the significance of TCR contacts with the MHC framework in direct allorecognition. In addition, the TCR diversity mobilized by this interaction and the massive TCRbeta mRNA accumulation observed after a few days of culture suggest that a significant proportion of naive T cells receive a signal leading to TCRbeta transcriptional activation even though only a few of them engage in mitosis.

Animals↗
PubMed2001

Mechanisms of tolerance induction: blockade of co-stimulation.

Induction of tolerance to transplantation antigens is believed to be a promising way to achieve long-term allograft survival without a deleterious immunosuppressive regimen. T-cell activation, which is an essential feature of graft rejection, requires a first signal provided by T-cell receptor (TCR) ligation and a second signal provided by engagement of co-stimulatory molecules with their respective ligands on antigen-presenting cells. The coordinated triggering of these two independent signalling systems ensures the full T-cell activation, including proliferation and acquisition of effector function. TCR occupancy in the absence of co-stimulatory signals leads to a sustained loss of antigen responsiveness called clonal anergy, which could be of major importance in transplantation. In vivo, co-stimulation blockade was indeed shown to allow for long-term allograft survival in several transplantation models. However, the current continuous identification of new co-stimulatory molecules suggests that a functional redundancy of the system exists and that tolerance to transplantation antigens might be achieved more easily through the combined blockade of two or several co-stimulatory signals. In this review, we analyse the biological effects of the disruption of some co-stimulation pathways in vitro and in vivo and discuss their potential interest for tolerance induction.

Animals↗
PubMed2001

Lethal hepatitis after gene transfer of IL-4 in the liver is independent of immune responses and dependent on apoptosis of hepatocytes: a rodent model of IL-4-induced hepatitis.

The putative role of IL-4 in human and animal models of hepatitis has not yet been directly determined. We now report that direct expression of IL-4 in the liver of rats or mice using recombinant adenoviruses coding for rat or mouse IL-4 (AdrIL-4 and AdmIL-4, respectively) results in a lethal, dose-dependent hepatitis. The hepatitis induced by IL-4 was characterized by hepatocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induced hepatitis was independent of T cell-mediated immune responses. Hepatitis occurred even after gene transfer of IL-4 into nude rats, CD8-depleted rats, cyclosporine A-treated rats, or recombinase-activating gene 2(-/-) immunodeficient mice. Peripheral depletion of leukocytes using high doses of cyclophosphamide, and/or the specific depletion of liver macrophages with liposome-encapsulated dichloromethylene diphosphonate in rats did not block lethal IL-4-induced hepatitis. Direct transduction of hepatocytes with adenoviruses was not essential, since injection of AdrIL-4 into the hind limb induced an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent hepatitis was associated with increases in the intrahepatic levels of IFN-gamma, TNF-alpha, and Fas ligand. Administration of AdmIL-4 to IFN-gamma, TNF-alpha receptor type I, or TNF-alpha receptor type II knockout mice also resulted in lethal hepatitis, whereas a moderate protection was observed in Fas-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolished by treatment with caspase inhibitory peptides. Our results thus demonstrate that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-1-Fas signaling and is largely independent of any immune cells in the liver.

Acute Disease↗
PubMed2001

Antigraft antibody-mediated expression of metalloproteinases on endothelial cells. Differential expression of TIMP-1 and ADAM-10 depends on antibody specificity and isotype.

Endothelial cell (EC) interaction with antigraft antibodies (Abs) mediates EC injury and activation involved in vascular graft rejection. The aim of this study was to identify EC genes regulated in response to antigraft Ab binding that contribute to the endothelium alterations implicated in graft rejection or survival. By means of RNA differential display, 13 cDNA fragments corresponding to genes differentially expressed in ECs incubated with antigraft Abs were identified. Among these cDNAs were found the tissue inhibitor of metalloproteinase-1 (TIMP-1) and a desintegrin and metalloproteinase (ADAM-10). We demonstrated that TIMP-1 and ADAM-10 mRNA and protein expression was rapidly upregulated in ECs in response to antigraft Ab binding. Our data showed that TIMP-1 was upregulated in response to human IgG but not IgM and anti-galactosyl (Gal) alpha1-3Gal human xenogeneic Abs. In contrast, upregulation of ADAM-10 in ECs was shown to be mostly mediated by anti-Galalpha1-3Gal IgM Abs. Specific effects of human IgG and IgM xenogeneic Abs on endothelial transcripts indicate that different isotypes and specificities of Abs may mediate different EC changes. Our results suggest that interaction of ECs with antigraft Abs, according to their specificity, selectively induces synthesis and release of metalloproteinases and inhibitors, controlling proteolytic processes and immunological events that respectively contribute to graft rejection or survival.

Amyloid Precursor Protein Secretases↗
PubMed2001

TGF-beta1 and donor dendritic cells are common key components in donor-specific blood transfusion and anti-class II heart graft enhancement, whereas tolerance induction also required inflammatory cytokines down-regulation.

Heart allograft tolerance in adult recipients can be induced in the LEW.1W to LEW.1A congeneic strain combination by pre-graft donor-specific blood transfusion (DST). Long-term survivors accept LEW.1W graft but reject third party skin grafts. As tolerant recipients of heart allografts showed an increase in anti-donor class II antibodies, we hypothesize that these antibodies could be instrumental in tolerance induction. However, anti-donor MHC class II alone prolonged graft survival but did not induce heart allograft tolerance in this combination. We analyzed the immune response patterns in heart allograft recipients following the injection of anti-donor class II antibodies (prolongation) or DST priming (tolerance). As suggested by the different phenomena, several immunological patterns were strikingly different between the two models. In strong contrast to DST-tolerant recipients, at 5 days after transplantation, neither Th1/Th2 nor inflammatory cytokines were inhibited in recipients treated with anti-donor class II antibodies, in which only prolongation of graft survival was induced. Nevertheless, in both models, depletion of resident dendritic cells (DC) from donor hearts inhibited tolerance induction (DST) or shortened allograft survival (anti-donor class II antibodies). Moreover, TGF-beta1 was not down-regulated and administration of neutralizing anti-TGF-beta1 antibody, which inhibited tolerance induction (DST), also shortened allograft survival (anti-donor class II antibodies). These results suggest that, in these two MHC class II-restricted models, both TGF-beta1 and donor DC have a pivotal role in prolonging graft survival. However, in the days following transplantation, further inhibition of inflammatory cytokine production, particularly Th1 and macrophage-derived cytokines is required for tolerance induction.

Animals↗
PubMed2001

Identification of immunodominant donor MHC peptides following rejection and donor strain transfusion-induced tolerance of heart allografts in adult rats.

Pre-graft priming of heart allograft recipients with donor strain blood induces tolerance in 100% of adult rats in the congenic LEW.1W to LEW.1A combination. This tolerant state is specific for donor MHC antigens as third-party blood transfusions fail to induce tolerance, and third-party skin grafts are promptly rejected by tolerant graft recipients. In this study we have characterized the immunodominant donor (RT1u) class I and II allogenic peptides which elicit an in vitro proliferative response to splenocytes from recipients (RT1a) undergoing acute rejection or tolerant to a LEW.1A cardiac allograft. Paradoxically, splenocytes from tolerant animals responded more vigorously to a broader set of donor peptides than splenocytes from rejecting animals. In addition, several of these peptides were observed to be stimulatory only for tolerant splenocytes. These findings suggest that regulatory cells may be involved in tolerance induction or maintenance and are selected by specific motifs, which could be utilized for manipulating the immune system of graft recipients.

Amino Acid Sequence↗
PubMed2001

Different mechanisms mediate the rejection of porcine neurons and endothelial cells transplanted into the rat brain.

In order to investigate the early cellular responses mediating xenograft rejection in the brain, porcine aortic endothelial cells (PAEC) or porcine fetal mesencephalic neurons (PNEU) were transplanted into the striatum of LEW.1A rats. PAEC were detected with a specific anti-beta1 integrin antibody, and PNEU with an anti-porcine neurofilament antibody, or an antibody recognizing the NeuN antigen. PAEC grafts were massively infiltrated within 24 h by OX42-positive cells, which may correspond to polymorphonuclear (PMN) cells or macrophages. At that moment, the graft contained numerous cells expressing the inducible isoform of NO-synthase (iNOS). Infiltration by ED1-positive macrophages was effective after three days. The beta1-integrin labeling decreased from that time-point to day 7 post-implantation, and vanished after 11 days. Although some OX8-positive cells were present around the graft as soon as 3 days after transplantation, cells expressing the T-cell receptor (TCR)-beta chain infiltrated the graft after 7 days and their number remained low. A strong, diffuse OX8-and ED1-positive immunoreactive material remained in the scar up to the third week. In striking contrast, PNEU grafts remained poorly infiltrated by OX42- or ED1-positive cells during the first two weeks. A massive infiltration by macrophages and TCRbeta-positive lymphocytes occurred after 3 weeks. Natural killer (NK) cells were more scarce. The inflammation territory enlarged, and blood vessels were overloaded with macrophages or lymphocytes. Nevertheless, the graft contained NeuN-positive nuclei and neurites harbouring the porcine neurofilament protein. Hence, rejection was not completed at this time-point. These results suggest that the rapid rejection of PAEC is mainly driven by macrophages and possibly PMN cells, unlike PNEU, whose rejection is delayed and also involves lymphocytes. Differences in immunogenicity of grafted cells and/or patterns of production of pro-inflammatory cytokines may account for these contrasted rejection kinetics.

Animals↗
PubMed2001

T-cell-mediated rejection of vascularized xenografts in the absence of induced anti-donor antibody response.

T cells are considered to play a major indirect role in the pathogenesis of xenograft vascular rejection, by promoting the induction of anti-donor antibodies that trigger complement- and antibody-dependent cell cytotoxicity. However, how vigorous the T cell xenoresponse is in vivo, and whether, besides their helper function, T cells are capable of directly affecting the graft is still unclear. We have previously shown that cyclosporine A (CsA) withdrawal in accommodated cardiac xenograft recipient allows for a rapid and dense T-cell infiltration, concomitant to an acute graft rejection. In this paper we further characterize the role of T cells in this rejection process and we demonstrate that adoptive transfer of CD4+ T cells in irradiated recipients of long-term cardiac xenografts is sufficient to trigger acute rejection, in the absence of any detectable induced anti-hamster antibody response. Therefore, our data suggest that unusually strong T-cell response will be another major barrier to xenotransplantation, even if antibody-mediated vascular rejection is controlled.

Adoptive Transfer↗
PubMed2001

Advances in transplant immunobiology.

The present review briefly addresses the most recent knowledge acquired in the field of transplant immunology. A particular emphasis is placed on articles published during the past 12-18 months that have focused on allorecognition, dendritic cells and tolerance.

Animals↗
PubMed2000

Cyclosporine inhibits class II major histocompatibility antigen presentation by xenogeneic endothelial cells to human T lymphocytes by altering expression of the class II transcriptional activator gene.

BACKGROUND: Cyclosporine (CsA) is currently given to recipients of vascularized xenografts as part of the immunosuppressive regimen required to prevent the hyperacute rejection phase. The effects of CsA on non-lymphoid immune cells, such as endothelial cells (ECs), have not been well characterized and sometimes seem contradictory, because both protective and adverse effects have been reported. In the present study, we investigated in vitro whether CsA could alter the antigenicity of activated porcine aortic endothelial cells (PAECs) by reducing class I and class II MHC antigen expression. METHODS: The effect of CsA on MHC antigen expression during tumor necrosis factor (TNF)-alpha- or lymphocyte-mediated PAEC activation was evaluated in vitro by flow cytometry and correlated to the ability of porcine ECs to promote human T lymphocyte proliferation. The effect of CsA on class II MHC antigen mRNA expression was also analyzed and related to class II transcriptional activator (CIITA) mRNA expression. RESULTS: Flow cytometry analysis showed that TNF-alpha-mediated induction of class II MHC antigen expression on PAECs was completely inhibited by CsA, whereas expression of class I MHC was reduced by 50%. The inhibition was dose dependent (at drug concentrations ranging from 2.5 microg/ml to 20.0 microg/ml) and was consistently observed at all time points (24-72 hr) during the activation period. Decreased MHC antigen expression dramatically reduced the ability of PAECs to further promote human T-cell proliferation. Similar levels of inhibition were achieved using an anti-porcine class II MHC blocking monoclonal antibody. Pretreatment of PAECs with CsA for 4 hr before coculture with human peripheral blood leukocytes efficiently blocked the induction on PAECs of E-selectin and class II MHC antigens and inhibited overexpression of class I antigens. Semiquantitative reverse transcriptase-polymerase chain reaction experiments showed that CsA markedly reduced the steady-state level of porcine class II (SLA-DRA and SLA-DQA) mRNA at 16 hr, compared with PAECs stimulated with TNF-alpha alone. The reduced level of class II MHC mRNA was associated with a lack of CIITA expression at this time point, suggesting that CsA could alter transcription or promote the rapid decay of CIITA mRNA. CONCLUSION: Our study indicates that CsA could play a role in preventing porcine MHC antigens being directly presented to human T lymphocytes by xenogeneic ECs.

Animals↗
PubMed2000

Anti-TCR-specific DNA vaccination demonstrates a role for a CD8+ T cell clone in the induction of allograft tolerance by donor-specific blood transfusion.

Donor-specific allograft tolerance can be induced in the adult rat by pregraft donor-specific blood transfusion (DST). This tolerance appeared to be mediated by regulatory cells and to the production of the suppressive cytokine TGF-beta1. A potential immunoregulatory CD8+ clone bearing a Vbeta18-Dbeta1-Jbeta2.7 TCR gene rearrangement was previously identified in DST-treated recipients. To assess the functional role of this T cell clone in the induction of tolerance by DST, we have vaccinated DST-treated recipients with a plasmid construct encoding for the Vbeta18-Dbeta1-Jbeta2.7 TCR beta-chain. DST-induced allograft tolerance was abolished by anti-TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination in six of seven recipients, whereas vaccination with the vector alone, or with the construct encoding a TCR Vbeta13 beta-chain, had no effect. However, the transcript number of the Vbeta18-Dbeta1-Jbeta2.7 chain was unchanged in allografts from vaccinated DST-treated rats, suggesting that this clone was not depleted by vaccination, but rather was altered in its function. Moreover, TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination restored the anti-donor alloantibody production, partially restore the capacity of spleen cells from tolerized recipients to proliferate in vitro against donor cells, and decreased the inhibitory effect of TGF-beta1, seen in DST-treated recipients, in spleen cells from vaccinated DST-treated ones. This study strongly suggests that this CD8+ TCR Vbeta18-Dbeta1-Jbeta2.7 T cell clone has an effective immunoregulatory function in allograft tolerance induced by DST.

Animals↗
PubMed2000

Tolerance to cardiac allografts via local and systemic mechanisms after adenovirus-mediated CTLA4Ig expression.

Blockade of the CD28/B7 T cell costimulatory pathway prolongs allograft survival and induces tolerance in some animal models. We analyzed the efficacy of a CTLA4Ig-expressing adenovirus in preventing cardiac allorejection in rats, the mechanisms underlying heart transplant acceptance, and whether the effects of CTLA4Ig were restricted to the graft microenvironment or were systemic. CTLA4Ig gene transfer into the myocardium allowed indefinite graft survival (>100 days vs 9 +/- 1 days for controls) in 90% of cases, whereas CTLA4Ig protein injected systemically only prolonged cardiac allograft survival (by up to 22 days). CTLA4Ig could be detected in the graft and in the serum for at least 1 year after gene transfer. CTLA4Ig gene transfer induced local intragraft immunomodulation at day 5 after transplantation, as shown by decreased expression of the IL-2R and MHC II Ags; decreased levels of mRNA encoding for IFN-gamma, inducible NO synthase, and TGF-beta; and inhibited proliferative responses of graft-infiltrating cells. Systemic immune responses were also down-modulated, as shown by the suppression of Ab production against donor alloantigens and cognate Ags, up to at least 120 days after gene transfer. Alloantigenic and mitogenic proliferative responses of graft-infiltrating cells and total splenocytes were inhibited and were not reversed by IL-2. In contrast, lymph node cells and T cells purified from splenocytes showed normal proliferation. Recipients of long-term grafts treated with adenovirus coding for CTLA4Ig showed organ and donor-specific tolerance. These data show that expression of CTLA4Ig was high and long lasting after adenovirus-mediated gene transfer. This expression resulted in down-modulation of responses against cognate Ags, efficient suppression of local and systemic allograft immune responses, and ultimate induction of donor-specific tolerance.

Abatacept↗