[Pathogenesis of ANCA-associated vasculitides in 2021: An update]. / Pathogénie des vascularites associées aux ANCA en 2021 : mise au point.

Anticytoplasmic neutrophil antibodies (ANCA)-associated vasculitis (AAV) are rare systemic immune-mediated diseases characterized by small vessel necrotizing vasculitis and/or respiratory tract inflammation. Over the last 2 decades, anti-MPO vasculitis mouse model has enlightened the role of ANCA, neutrophils, complement activation, T helper cells (Th1, Th17) and microbial agents. In humans, CD4T cells have been extensively studied, while the dramatic efficacy of rituximab demonstrated the key role of B cells. Many areas of uncertainty remain, such as the driving force of GPA extra-vascular granulomatous inflammation and the relapse risk of anti-PR3 AAV pathogenesis. Animal models eventually led to identify complement activation as a promising therapeutic target. New investigation tools, which permit in depth immune profiling of human blood and tissues, may open a new era for the studying of AAV pathogenesis.

Rat spleen dendritic cells express natural killer cell receptor protein 1 (NKR-P1) and have cytotoxic activity to select targets via a Ca2+-dependent mechanism.

Dendritic cells (DC) are a subset of leukocytes whose major function is antigen presentation. We investigated the phenotype and function of enriched (95-98.5%) rat DC. We show that both spleen and thymus DC express the natural killer cell receptor protein 1 (NKR-P1) as a disulfide linked homodimer of 60 kD. Freshly isolated DC express a low level of NKR-P1, which is strongly upregulated after overnight culture. Spleen, but not thymus DC, were able to kill the NK-sensitive YAC-1 cell line in vitro, and since this killing was Ca2+ dependent, a Fas ligand-Fas interaction was probably not involved. Besides their potent antigen-presenting function, DC can thus be cytotoxic for some tumor targets.

TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation.

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4(+) T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4(+) T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4(+) T cell responses that produce normal levels of interferon gamma, suggesting a CD40L/CD40-independent mechanism of CD4(+) T cell priming that to date has not been elucidated. Here we show that CD4(+) T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4(+) T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4(+) T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention.

TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo.

Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.

TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor.

TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine) is a new member of the TNF family that is induced upon T cell receptor engagement and activates c-Jun N-terminal kinase (JNK) after interaction with its putative receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid organs and T cells. Here, we show that high levels of TRANCE-R are detected on mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor-associated factor 2 (TRAF2), since JNK induction is impaired in cells from transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits apoptosis of mouse bone marrow-derived DCs and human monocyte-derived DCs in vitro. The resulting increase in DC survival is accompanied by a proportional increase in DC-mediated T cell proliferation in a mixed leukocyte reaction. TRANCE upregulates Bcl-xL expression, suggesting a potential mechanism for enhanced DC survival. TRANCE does not induce the proliferation of or increase the survival of T or B cells. Therefore, TRANCE is a new DC-restricted survival factor that mediates T cell-DC communication and may provide a tool to selectively enhance DC activity.

Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE.

Proper lymph node (LN) development requires tumor necrosis factor-related activation-induced cytokine (TRANCE) expression. Here we demonstrate that the defective LN development in TRANCE(-/)- mice correlates with a significant reduction in lymphotoxin (LT)alphabeta(+)alpha(4)beta(7)(+)CD45(+)CD4(+)CD3(-) cells and their failure to form clusters in rudimentary mesenteric LNs. Transgenic TRANCE overexpression in TRANCE(-/)- mice results in selective restoration of this cell population into clusters, and results in full LN development. Transgenic TRANCE-mediated restoration of LN development requires LTalphabeta expression on CD45(+) CD4(+)CD3(-) cells, as LNs could not be induced in LTalpha(-/)- mice. LTalpha(-/)- mice also showed defects in the fate of CD45(+)CD4(+)CD3(-) cells similar to TRANCE(-/)- mice. Thus, we propose that both TRANCE and LTalphabeta regulate the colonization and cluster formation by CD45(+) CD4(+)CD3(-) cells in developing LNs, the degree of which appears to correlate with the state of LN organogenesis.

Indirect CD4+ TH1 response, antidonor antibodies and diffuse C4d graft deposits in long-term recipients conditioned by donor antigens priming.

Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.D(u) molecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4+ indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibody-mediated rejection in human.

A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance.

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in humans and animals but the immunological mechanisms of this effect remain unclear. We have analyzed the expression and the role of endogenous TGF-beta1 in a model of heart allograft tolerance, induced by pregraft DST in adult rats. We reported previously that this tolerance occurs despite a strong infiltration of leukocytes into the graft that are unable to produce both Th1- and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGF-beta1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGF-beta1. TGF-beta1-producing cells are virtually absent among early infiltrating cells in rejected grafts but are found at a later time point. The induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti-TGF-beta mAb. Moreover, overexpression of active TGF- beta1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGF-beta as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGF-beta-producing regulatory cells are also involved in allograft tolerance.

IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis.

Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.

TRANCE is a TNF family member that regulates dendritic cell and osteoclast function.

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a new member of the TNF family emerging as a key regulator of the immune system and of bone development and homeostasis. TRANCE is expressed on activated T cells and activates mature dendritic cells (DC), suggesting that it plays a role in the T cell-DC interaction during an immune response. Furthermore, TRANCE is expressed on osteoblasts stimulated with vitamin D3, dexamethasone, and parathyroid hormone. TRANCE, when expressed on osteoblasts, induces osteoclastogenesis and osteoclast activation, suggesting that it links known calciotropic hormones to bone resorption. TRANCE mediates its effects via the TRANCE-receptor (TRANCE-R/RANK), whereas its activity can be inhibited by the soluble decoy receptor osteoprotegerin/osteoclast inhibitory factor (OPG/OCIF). OPG can be neutralized by another TNF-family member, the TNF-related apoptosis-inducing ligand (TRAIL), suggesting that TRANCE is part of a complex cytokine network that regulates a diverse set of functions. We will discuss the current literature describing TRANCE and its receptors and its role in controlling DC and osteoclast function.

The influence of HLA A-B-DR matching on cytomegalovirus disease after renal transplantation. Evidence that HLA-DR7-matched recipients are more susceptible to cytomegalovirus disease.

We examined the prevalence of cytomegalovirus infectious episodes, as defined by clinical, virological, and serological criteria (i.e., CMV disease), in 660 kidney graft recipients; 109 patients (16.5%) developed the disease, and 551 did not. No significant statistical link between CMV disease prevalence and a given HLA-A, -B, or -DR allele was observed. However, patients with HLA-DR7 matched grafts were statistically more frequently found (P < 0.01) in the group of recipients who developed CMV disease as compared with the group who did not develop CMV disease. Furthermore, among patients who developed CMV disease, a significant increase of HLA-DR7 matched over DR7 mismatched patients was noted, whereas no difference between matched and mismatched recipients for the other HLA-DR alleles was found. No difference in the severity of graft failure, often observed during, or immediately after, the CMV episode, was noted between patients matched or mismatched for HLA-DR7. Our data suggest that donor/recipient matching for HLA-DR7 is associated with increased CMV disease.

T cell receptor repertoire usage in allotransplantation: an overview.

Lymphocytes express antigen receptors that allow the immune system to specifically recognize antigens. In transplantation, T cells play a critical role in the rejection process, and different protocols inhibiting T cell-mediated alloreactivity efficiently achieve prolongation of allograft survival. T cells can interact with alloantigens by two ways, either by the "indirect" pathway that correspond to the physiological mechanism of T cell immune recognition, or through the "direct" pathway where they recognize alloantigens directly on the surface of donor cells. If some T cells are specifically activated in allorecognition, one should be able to indirectly detect this "selection" by analyzing the T cell receptor usage that could be biased and reflect the preferential amplification of alloreactive lymphocyte subsets. Nevertheless compared with disease states such as cancer or autoimmunity the T cell receptor repertoire is still largely uncharacterized. We review the current results available on T cell repertoire usage in transplantation studies involving humans or various animal models. The T cell receptor repertoire involved in transplantation (restricted or unrestricted) and the features potentially common to alloimmune responses will be discussed.

Prolongation of allogeneic heart graft survival in rats by administration of a peptide (a.a. 75-84) from the alpha 1 helix of the first domain of HLA-B7 01.

Allospecific T lymphocytes mediate graft rejection through specific, direct or indirect, recognition of processed determinants of foreign MHC class I molecules. Small synthetic peptides derived from highly conserved sequences of the alpha 1 helix of the first domain of certain MHC class I molecules have been shown to inhibit CTL responses in vitro and to prolong graft survival in rats when combined with subtherapeutic doses of cyclosporine. Here, we report that the survival of LEW.1W heart allografts was significantly prolonged when transplanted into congenic LEW.1A recipients treated only with a peptide corresponding to residues 75-84 of the human HLA-B7-01 molecule (B7.75-84) before transplantation. The experimental value for mean survival time (+/- SD) in untreated recipients was 13 +/- 6 days and in peptide-treated recipients was 42 +/- 27 days (P < 0.002). A total of 64% of treated recipients had a functioning graft at 30 days, while grafts were rejected in all rats belonging to the control group within this time. Within graft-infiltrating leukocytes (GIL) in B7.75-84-treated animals, the proportion of T cells was significantly lower and that of CD5-/TCR alpha beta-/CD16-/CD8+ and MHC class II+ cells concomitantly increased, as compared with nontreated animals. GIL from B7.75-84-treated animals also exhibited a dramatic decrease (approximately 70%) of allospecific and spontaneous (NK) cytotoxic activity, whereas their proliferation and IL-2 production were similar in both experimental groups. The IFN-gamma, IL-2, and IL-10 mRNA levels from GIL from peptide-treated recipients were similar to levels of controls, reflecting a state of activation of GIL. Perforin and granzyme A mRNA, the level of which may be modulated parallel to impaired cytotoxic functions, were at similar levels in both experimental groups. These data demonstrate that B7.75-84 significantly prolongs graft survival in LEW.1A rats when given as a single agent and suggests that a specifically decreased cytotoxic response (allospecific and spontaneous) plays a major role.

Graft-infiltrating T helper cells, CD45RC phenotype, and Th1/Th2-related cytokines in donor-specific transfusion-induced tolerance in adult rats.

Specific tolerance to LEW.1W (RT1u) heart allografts can be induced in adult LEW.1A (RT1a) rats by donor-specific blood transfusion (DST). We have previously shown that both rejected and tolerated grafts are heavily infiltrated by T lymphocytes, and that in both cases these T cells are capable of developing similar cytotoxic responses against donor cells in vitro; tolerance is therefore not due to the deletion of alloreactive T cells. At the same time, we found that the accumulation of IL-2 and IFN-gamma mRNA was decreased in tolerated grafts compared with rejected grafts. These results suggested that the induction of allograft tolerance in DST-treated animals could be mediated by anergy or suppression of graft-infiltrating Th1 cells. Although Th1 and Th2 clones have not yet been characterized in the rat, peripheral CD4+ rat T cells can be divided into two populations, based on their expression of the isoform RC of the CD45 molecule. Upon activation, CD45RChigh CD4+ T cells produce IL-2 and IFN-gamma and responsible for the induction of the graft-versus-host reaction, whereas CD45RClow CD4+ T cells produce IL-4 in vitro and provide B cell help. In the present study, we show that heart allografts from both DST-treated and untreated rats were infiltrated by equivalent numbers of leukocytes, of which CD4+ T cells also made up similar percentages. Among these CD4+ T cells, we observed that in allografts from DST-treated recipients the CD45RChigh population on day 5 was very significantly smaller (P = 0.004) than in the untreated group, while CD45RClow populations remained comparable. Moreover, using a new quantitative RT-PCR method, we found a dramatic reduction in the accumulation of IL-2, IFN-gamma, IL-10, IL-4, and IL-13 mRNA in hearts from DST-treated recipients compared with those of untreated recipients during the week following transplantation. These results show that in heart allografts from DST-treated recipients, despite phenotypic changes suggesting Th1 inhibition by Th2 imbalance, T helper function was inhibited as a whole, and that in vivo the phenotype CD4+ CD45RClow does not always correlate with Th2-related cytokine-producing cells.

Fas ligand, tumor necrosis factor-alpha expression, and apoptosis during allograft rejection and tolerance.

BACKGROUND: Cytotoxic T cells can induce target cell lysis and apoptosis by different pathways. The interactions of CD95 antigen (Fas) with its ligand (CD95L) and of tumor necrosis factor (TNF)-alpha with its receptor (TNF-R1) lead to apoptotic cell death. Recently, conflicting studies have been published concerning the expression and the role of CD95L in allograft rejection and tolerance. METHODS: In this study, the intragraft expression of CD95/CD95L and TNF-alpha and the frequency and distribution of apoptotic cells were compared in a model of heterotopic cardiac allograft in the rat in which recipients were either not treated (acute rejection) or pretreated with donor-specific blood transfusion (tolerant). RESULTS: In the acutely rejected allografts, a peak in the expression of CD95L and TNF-alpha and in the number of apoptotic cells was observed during the first week after transplantation; apoptotic cells were confined to graft-infiltrating cells. In the tolerated allografts, however, levels of graft-infiltrating cell apoptosis and CD95L and TNF-alpha expression during the same period of time were dramatically lower. The expression of Fas was constitutive and was not modulated during acute rejection or tolerance. CONCLUSION: This down-regulation of CD95L and TNF-alpha in allografts rendered tolerant by donor-specific transfusion suggests a role for apoptosis-inducing pathways in acute allograft rejection.

Decreased cytotoxic activity of natural killer cells in kidney allograft recipients treated with human HLA-derived peptide.

Peptides derived from a conserved region (aa 75-84) of HLA class I, overlapping the supertypic HLA-BW4/BW6 antigen region, have been shown to exhibit nonallele restricted immunosuppressive properties in rats and mice, prolonging survival of major histocompatibility complex-mismatched allografts. Furthermore, HLA-B7 peptides inhibit alloreactive cytotoxic cells, and both HLA-B7 and HLA-B2702 peptides inhibit natural killer (NK) cytotoxicity in vivo. In this article, we report on a randomized, controlled study of the safety and pharmacokinetics of HLA-B2702-derived peptide in human recipients of a first kidney allograft. Escalating doses of HLA-B2702 were compared with doses of placebo controls. No toxicity and no immunization against the peptide were noted. Although the study was not designed as an efficacy trial, patients who received the high-dose protocol (7 mg/kg) did experience more rejection episodes, but this was not statistically significant when compared with control patients. Interestingly, in human recipients, as previously observed in rodents, administration of the peptide was associated with a statistically significant decrease in the cytotoxicity of NK cells against K562 targets (P<0.001). As these peptides correspond to a region of the HLA class I molecule that interacts with the newly described NK receptors for class I, their mode of action through interaction with such receptors is discussed. As a peptide of the same sequence from HLA-B7 blocks both NK and alloreactive T cell cytotoxicity, it is possible that, in humans too, both types of cytotoxic cells are affected by this peptide. The biological significance of these observations should be confirmed in future controlled studies with a larger patient population.

Modulation of hyperoxia-induced TNF-alpha expression in the newborn rat lung by thalidomide and dexamethasone.

The effect of high oxygen concentrations on lungs of neonatal rats was studied. In addition, some oxygen-exposed animals were treated with either dexamethasone or thalidomide. No gross histologic changes were noted in the lungs following exposure to 95% oxygen nor were there changes in the total number or the phenotypic distribution of BAL cells obtained from these lungs compared to lungs from air exposed (control) neonatal rats. The majority of the BAL cells were CD45+ leukocytes (macrophages). However, when BAL cells were exposed to LPS in vitro, TNF-alpha production was higher in cells from rats exposed to 95% oxygen compared to cells from rats exposed to ambient air. In addition, lung TNF-alpha and IL-6 mRNA levels were increased after exposure to 95% oxygen. In the lungs of animals treated with either dexamethasone or thalidomide, TNF-alpha mRNA levels were reduced, while only dexamethasone treatment also reduced IL-6 mRNA levels.

Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid.

Interleukin-22 (IL-22) is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation, and cancer. IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DCs) in lymphoid and non-lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103(+)CD11b(+) DC. In humans, IL-22BP was expressed in immature monocyte-derived DC and strongly induced by retinoic acid but dramatically reduced upon maturation. Our data suggest that a subset of immature DCs may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP.