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PubMed2002

Indirect allorecognition can play an important role in the development of transplant arteriosclerosis.

BACKGROUND: Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. METHODS: Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG (-/-) mice. Immunodeficient mice were reconstituted with either CD4(+) (indirect) or CD8(+) (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. RESULTS: Reconstitution of athymic nude mice with 4 x 10(7) purified CD4(+) T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24+/-8% and did not decrease when nude-derived endogenous CD8(+) T cells were depleted from the nude recipients (intimal proliferation, 21+/-7%). Transplant arteriosclerosis initiated by CD4+ T cells was associated with the presence of intragraft mRNA for interferon-gamma, tumor necrosis factor-alpha, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1(-/-) mice with 4 x 10(7) purified CD4(+) T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20+/-9%) in MHC class I mismatched aortic grafts in the absence of alloantibody production. CONCLUSION: Indirect recognition of donor MHC class I molecules by CD4(+) T cells can play an important role in the process of transplant arteriosclerosis. CD8(+) T-cell effector function and alloantibody production in this model are dependent on CD4(+) T-cell help after indirect allorecognition.

Adoptive Transfer↗

PubMed1998

Assessment of the contribution that direct allorecognition makes to the progression of chronic cardiac transplant rejection in humans.

BACKGROUND: Two populations of T cells contribute to allograft rejection. T cells with direct allospecificity are activated after recognition of intact MHC alloantigens displayed at the surface of donor passenger leukocytes carried within the graft. In contrast, T cells with indirect allospecificity recognize donor alloantigens as processed peptides associated with self (recipient)-MHC class II molecules. In small animal models of transplantation, direct pathway T cells dominate the acute rejection process and are rendered tolerant to the graft after the loss of donor passenger leukocytes. It has been argued that indirect pathway T cells contribute substantially to continual graft damage after passenger cell loss. The purpose of this study was to determine whether donor-specific tolerance could be detected in T cells with direct anti-donor allospecificity in human heart transplant recipients after prolonged graft residence. METHODS AND RESULTS: Alloreactive helper (HTLf) and cytotoxic (CTLf) T cells were enumerated by use of limiting dilution analysis. These assay systems were refined to make them specific for the direct pathway of allorecognition and more sensitive in the case of the HTLf assay. Recipient:anti-donor frequencies were generated in 10 long-term recipients of heart grafts with progressive chronic rejection and compared with those against equivalently HLA mismatched recipient:third-party controls. For HTLf, direct pathway donor-specific hyporesponsiveness was detected in 5 of the 10 recipients (HTLf<1:100,000). Of these 5 recipients, 4 also had low anti-donor CTLf (<1:100,000). In the 5th recipient, although the CTLf was >1:100,000, it was significantly lower than that estimated against the third-party control. CONCLUSIONS: Donor-specific hyporesponsiveness is demonstrated in 50% of recipients in both the HTLf and CTLf compartments of the direct alloresponse. Direct allorecognition therefore appears unlikely to be responsible for the progression of chronic rejection, implicating indirect allorecognition as the predominant immunological driving force. Furthermore, these data have potential implications for graft outcome, adjustment of immunosuppression, and recipient monitoring.

Antibody Specificity↗

PubMed2002

Hierarchical contributions of allorecognition pathways in chronic lung rejection.

The role of allorecognition in initiating lung graft rejection is not clearly defined. Using the heterotopic tracheal transplantation model, we examined the contributions of the indirect and direct allorecognition pathways in chronic airway rejection. Fully mismatched, wild-type grafts were transplanted into major histocompatibility complex (MHC) II-/-, class II-like accessory molecule (H2-DMalpha)-/- using MHC I-/- and wild-type allorecipients as control subjects. Similarly, MHC I-/-, MHC II-/-, or MHC I/II-/- allografts were transplanted into wild-type mice with appropriate control subjects. Grafts from nonimmunosuppressed recipients were evaluated at Weeks 2, 4, and 6. Grafts transplanted into MHC II-/- and H2-DMalpha-/- allorecipients showed a more intact epithelium and reduced lumen obliteration compared with grafts transplanted into wild-type or MHC I-/- allorecipients (p < 0.05 for each). These grafts exhibited abundant CD4+ and CD8+ cell infiltrates similar to control allografts. MHC I-/- and MHC I/II-/- but not MHC II-/- allografts placed in wild-type animals demonstrated less severe rejection compared with allograft control subjects (p < 0.05 for each). Although the indirect allorecognition pathway has the strongest influence on rejection, the direct pathway is sufficient to ultimately cause chronic airway rejection. In addition, these results suggest that MHC class I molecules are the principal alloantigens in the mouse heterotopic tracheal model of obliterative bronchiolitis.

Animals↗

PubMed2001

Indirect allorecognition of donor class I and II major histocompatibility complex peptides promotes the development of transplant vasculopathy.

Recent clinical and experimental evidence suggests that indirect allorecognition may promote the development of chronic rejection, but definitive experimental studies are lacking. To study the contribution of indirect allorecognition to chronic rejection, naïve Lewis (RT1(1)) rats were immunized with synthetic Wistar Furth (WF) class II-RT1(u).D (HLA-DR-like) or -RT1(u).B (HLA-DQ-like) or class I-RT1(u).A (HLA-A-like) peptides emulsified in complete Freund's adjuvant 7 d before transplantation (n = 5 to 7/group). Experimental and control animals then acted as recipients of fully mismatched WF vascularized cardiac allografts. Recipients received immunosuppression in the form of cyclosporine at a tapering dose that allows for long-term allograft survival. Animals were sacrificed at either 3 or 6 mo, with allograft arterial luminal occlusion scored on elastin stains by a blinded observer. At 3 mo, mean vessel scores were significantly higher in the RT1(u).A-immunized versus class II-immunized and control groups (P < 0.05). By 6 mo, there was progression of chronic allograft vasculopathy and a significantly higher mean vessel score in the RT1(u).A- and RT1(u).D-immunized versus RT1(u).B and control groups (P < 0.05). In vitro studies show evidence of shifting MHC allopeptide immunogenicity. It was concluded that T cells primed by specific donor class I and II MHC allopeptides promote the development of chronic vascularized allograft rejection. These novel observations provide definitive evidence of a link between indirect allorecognition and the development and progression of chronic rejection.

Animals↗

PubMed2002

The ontogeny of allorecognition in a colonial hydroid and the fate of early established chimeras.

Colonies of the marine hydroid, Hydractinia, are able to discriminate between their own tissues and those belonging to unrelated conspecifics. We have studied the ontogeny of this allorecognition system by a series of allogeneic transplantations along a developmental gradient, including two-cell-stage embryos, 8 h morulae, planula larvae and metamorphosed polyps. Allograft acceptance of incompatible tissue was observed in all embryonic and larval stages, whereas metamorphosed polyps rejected incompatible transplanted allografts. Most of the chimeras established at the two-cell-stage, although composed of two allogeneic, incompatible entities with mismatching allorecognition loci, developed normally and remained stable through metamorphosis. The results of post metamorphic transplantation assays among the chimeras and the naive ramets, suggested that both incompatible genotypes were still represented in the chimera despite the onset of alloimmune maturation. The naive colonies always rejected each other. Chimeras established from later embryonic and larval stages did not develop into adult chimeric entities, but rather separated immediately post metamorphosis. We thus show that (1) allorecognition in this species matures during metamorphosis and (2) genetically incompatible entities may coexist in one immunologically mature, chimeric soma, provided that they were grafted early enough in ontogeny.

Animals↗

PubMed1987

Role of natural killer (NK) cells in the production of the murine T lymphocyte allorecognition repertoire.

Limiting dilution cultures of alloreactive (anti-H2Kb) CTL were established from thymocyte or spleen cell pools of C3H/HeJ and their congenic bg/bg partner, or of SJL/J and their congenic bg/bg partner. CTL populations in these cultures were assayed for cross-reactive lysis of a panel of splenic Con A blasts of H2Kbm mutant mice. There was some slight elevation of frequency of CTLp in the thymocyte lymphoid pool of bg/bg mice; more strikingly, the repertoire of anti-H2Kb specificities was clearly altered in both strains in the bg/bg animals. There was apparently an increased diversity (more specificities represented at higher frequencies) in the thymocyte pool and a decreased diversity in the spleen cell CTLp pool in animals with the bg/bg marker. Similar shifts in the allorecognition repertoire of normal C3H/HeJ mice were produced by inoculation of neonatal mice with a rabbit anti-NK heteroantibody (antiasialo GM1). Preabsorption of this serum such that it lost anti-NK activity also abolished this effect of in vivo neonatal injection. Furthermore, injection of bg/bg bone marrow-reconstituted C3H/HeJ (bg/+) mice with a C3H spleen cell-derived NK line also caused a shift in the allorecognition repertoire toward that seen in the normal littermate control animals.

Animals↗

PubMed1990

Mutations in the alpha 1 domain of a class I gene define residues important for specific allorecognition.

Our strategy to use saturation mutagenesis to produce an unbiased collection of major histocompatibility class I mutants has resulted in unpredicted mutant phenotypes. First, we have shown data supporting our earlier work of the Dp20(Y27N) mutant. Allorecognition is altered at the clonal level while no variation in lymphocytic choriomeningitis virus (LCMV)-restricted recognition is observed. The defect does not destroy the integrity of this class I protein on the basis of three observations: (i) LCMV self-restricted recognition is not impaired, (ii) beta 2 microglobulin still associates with Dp20(Y27N) at the cell surface, and (iii) this mutant can stimulate a primary MLR. Thus, we believe Dp20(Y27N) specifically affects allorecognition, perhaps by altering self peptide associations. The Dp14(A11V;E32Q) mutant appears to interact with T cell receptors (TCR) from a cloned cytotoxic T lymphocyte, but is altered in inducing a wild type signal into the responding cell. This is presumably due to decreased interaction at the cell surface between Dp14(A11V;E32Q) and wild type-specific TCR such that variations are detected in how a cell perceives extracellular signals. Analysis of additional mutants suggests that mutant Dp163(N66S) alters the binding site for monoclonal antibodies 7-16.10 and 135, while leaving unaltered the binding site for monoclonal antibodies 34-1.2 and 11-20.3. This maps the residue responsible for 7-16.10 and 135 binding to the region of Dp163(N66S).

Animals↗

PubMed1996

The TAP complex influences allorecognition of class II MHC molecules.

The influence of the TAP complex on T-cell allorecognition of MHC class II molecules was examined using human B-cell lines that have mutations in the TAP 1 or 2 genes. The TAP mutations led to the loss of allorecognition for two of 28 anti- HLA-DR T-cell clones. Restoration of TAP expression by transfection of a TAP 2 cDNA clone led to recovery of the alloresponse for both clones. These results could be explained in two ways. First, TAP dependence could reflect specificity for a peptide derived from an MHC class I molecule that is less efficiently generated by the endocytic pathway in the TAP-deficient stimulator cells owing to reduction in surface class I expression. The proliferative responses of these clones to the TAP-deficient stimulator cells was not restored by rescue of cell-surface expression of class I molecules by low temperature culture or by the addition of class I-binding peptides. These data therefore favor the alternative explanation that class II loading by some peptides is TAP dependent. Circumstances that lead to the amplification of this minority pathway of endogenous presentation by class II MHC molecules may have the potential to interrupt self-tolerance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1991

Structural aspects of allorecognition.

The phenomenon of T-cell allorecognition of foreign major histocompatibility molecules has been one of the more enigmatic aspects of T-cell immunology. The molecular basis for allorecognition is unfolding as a result of the application of major histocompatibility complex structure/function analyses in the light of current insights into the three-dimensional structure of major histocompatibility complex products.

Animals↗

PubMed1993

Indirect T cell allorecognition: a cyclosporin A resistant pathway for T cell help for antibody production to donor MHC antigens.

LEW (RT1(1)) rats were primed for indirect allorecognition of DA (RT1avl) MHC molecules by immunizing either with synthetic peptides corresponding to the polymorphic regions of the RT1.Aavl classical class I MHC molecule, or with the isolated, denatured chains of the RT1.A class I, RT1.B alpha class II and RT1.B beta class II MHC molecules of the DA strain. These primed LEW rats received DA kidney allografts and were treated after grafting with cyclosporin A. Unprimed LEW controls mount a vigorous rejection response to DA kidney allografts and produce a strong antibody response to DA class I MHC antigens. Both the rejection and the antibody responses are virtually completely suppressed by cyclosporin A treatment in these controls. Priming to indirect allorecognition of donor MHC antigens did not diminish the effectiveness of cyclosporin A in suppressing the acute rejection of DA kidney grafts, but cyclosporin A could not suppress the early antibody response to the grafts in the primed rats. This finding could be of importance in clinical transplantation, where antibody-mediated graft damage might play an important role in both acute vascular rejection and chronic rejection.

Animals↗

PubMed2006

Allorecognition in urochordates: identification of a highly variable complement receptor-like protein expressed in follicle cells of Ciona.

The evolutionary origin of allorecognition in vertebrates is unknown. Urochordates, being the closest living relatives of vertebrates [Delsuc F, Brinkmann H, Chourrout D, Philippe H]. Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature 2006; 439: 965-8], have efficient mechanisms to prevent both allogeneic fusion and self fertilization. To shed light on allorecognition in urochordates and on the molecules involved in preventing self fertilization, we compared gonadal cDNAs of three genetically unrelated Ciona intestinalis individuals by suppression subtractive hybridisation (SSH). Here, we report the discovery and characterization of a highly polymorphic gene coding for a transmembrane protein with several short consensus repeat domains (SCR/CCP). The protein, termed variable complement receptor-like 1 (vCRL1), is structurally similar to vertebrate complement receptors. However, in contrast to vertebrate complement receptors, vCRL1 shows an unprecedented high degree of amino acid variations among Ciona individuals and is expressed in follicle cells as well as in hemocytes. Based on our data we propose that in the absence of MHC Ciona uses variable components of the complement system as individuality markers.

Amino Acid Sequence↗

PubMed2004

Role of a KIR/HLA-C allorecognition system in pregnancy.

Decidual natural killer (NK) cells are thought to play a significant role in the allorecognition mechanisms during pregnancy. Through their activating and inhibitory receptors they may recognize selectively class I HLA alleles expressed on invading trophoblast and provide self-signals to control NK responses, thus regulating the maternal immune response at the fetomatenal interface. Killer immunoglobulin-like receptors (KIR) constitute one of the families of class I MHC receptors which are expressed on NK cells. Their repertoire includes both activating and inhibitory receptors, most of which recognize specific epitopes on HLA-C molecules and can either activate NK cell responses or abort activating signals and inhibit NK cell functions. Since KIRs are expressed on decidual NK cells and the HLA-C molecules that they recognize are also expressed on invading trophoblast, KIR receptors may play a regulatory role in pregnancy by interacting with their trophoblastic HLA-C counterparts and providing trophoblast damage evading signals (KIR/HLA-C allorecognition system). Our hypothesis that the KIR/HLA-C system might be ineffective in some unsuccessful pregnancies, has been investigated in women with unexplained spontaneous abortions. Our results suggest that a limited maternal repertoire of inhibiting KIRs (inhKIRs) and/or lack of maternal inhKIR-fetal HLA-C epitope matching may predispose to miscarriage.

Abortion, Spontaneous↗

PubMed2006

Tolerogenic response: allorecognition pathways.

The induction of immune tolerance in transplant recipients has been sought for many years but only a fundamental understanding of the immunological mechanisms underlying graft rejection will allow manipulation of the anti-graft immune response. In general, acute rejection is better understood and treated than chronic rejection, as they occur through partially different mechanisms. It is now generally accepted that recognition of same-species, non-self antigens (allorecognition) occurs through at least two different mechanisms, the direct and indirect pathways. In the direct pathway, donor MHC molecules on the surface of donor antigen-presenting cells (APCs) are recognised directly by the recipient's T cells. This mechanism is so immediate that it seems to be primarily involved in acute graft rejection. Since APCs of donor origin are depleted with time a second mechanism, the indirect pathway, takes over to cause chronic rejection, in which foreign MHC molecules are internalised, partially digested and presented as peptides to recipient T cells. Nonetheless, a number of studies are only fully understood when a third proposed allorecognition mechanism is taken into account. This is the semi-indirect pathway, as discussed in this short report.

Antigen-Presenting Cells↗

PubMed2003

Upregulation of IL-2 but not IL-15 by allorecognition in human mixed lymphocyte culture.

The redundant and pleiotropic effects of cytokines in transplant models have been shown both in vitro and in vivo. IL-2 is clearly not necessary for allograft rejection, possibly due to upregulated IL-15. We examined IL-15 expression using mixed lymphocyte culture (MLC) as an allorecognition model. IL-2 and IL-15 levels were measured by enzyme-linked immunoassay after 120 hours of culture. Cell proliferation in MLC was examined using [(3)H]thymidine uptake in the presence of either anti-IL-2Ralpha chain antibody or anti-IL-2Rgamma chain antibody. While IL-2 was detectable in cell supernates of MLC, IL-15 was not. Stimulation with an Anti-IL-2 gamma chain antibody which blocks the IL-2 gamma chain, a common unit in IL-2/IL-15 receptors, failed to produce additive antiproliferative effects after maximum inhibition by anti-IL-2alpha chain antibody, which is specific for IL-2. In conclusion, experiments in the MLC model suggest that allorecognition upregulates IL-2 but not IL-15 expression.

Cell Division↗

PubMed1996

Attempts to demonstrate indirect T cell allorecognition of donor MHC peptides in transplant patients.

Indirect T cell allorecognition has been shown to play an important role in the rejection of allografts in experimental animals. Although there has been much speculation as to its role in clinical transplantation, especially with regard to chronic rejection, indirect T cell allorecognition has been difficult to demonstrate in transplant patients. In this paper, we looked for in vitro T cell proliferation to synthetic peptides corresponding to donor HLA-A and HLA-B incompatible antigens. Twelve 15 amino acid peptides corresponding to the hypervariable regions of six of the most common HLA class I alleles in Caucasian populations (A1, A2, A3, B7, B8 and B44) were studied. Blood was taken from 12 adult patients following one or more episodes of acute kidney graft rejection, and from three pediatric patients undergoing chronic rejection of heart/lung transplants. The donor-recipient combinations were selected such that at least one of the six HLA antigens above was present in the donor and absent in the recipient. Peripheral blood mononuclear cells from these patients responded strongly in proliferation assays to phytohemagglutinin. However, none responded to the incompatible donor HLA peptides. Compartmentalization of responding T cells, the effects of immunosuppression, and assay sensitivity are discussed as possible explanations for the negative results.

Adult↗

PubMed2003

Concomitant allorecognition of mismatched donor HLA class I- and class II-derived peptides in pediatric lung transplant recipients with bronchiolitis obliterans syndrome.

BACKGROUND: The authors' previous studies with 2 different adult patient populations demonstrated a correlation between indirect allorecognition of mismatched donor HLA Class I- and Class II-derived peptides and the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. The aim of this study was to determine whether a parallel allorecognition of mismatched donor HLA Class I- and Class II-derived peptides occurs after lung transplantation and to determine its correlation with the development of BOS after lung transplantation in a group of pediatric patients. METHODS: Peripheral blood mononuclear cells from 7 BOS-positive and 6 BOS-negative pediatric lung transplant recipients (age, 11.5 +/- 4.4 years) were cultured in the presence of synthetic peptides corresponding to the alpha-chain hypervariable regions of a mismatched donor HLA Class I molecule and the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. The frequencies of HLA Class I and Class II alloreactive T cells were determined using limiting dilution analysis. RESULTS: A significant increase (p = 0.025) in HLA Class I-alloreactive T cells was observed in BOS-positive patients (7.1 x 10(-5) +/- 4.3 x 10(-5)) compared with BOS-negative patients (2.1 x 10(-5) +/- 1.8 x 10(-6)). In addition, a significant increase (p = 0.033) in HLA Class II-alloreactive T cells also was observed in BOS-positive patients (9.6 x 10(-5) +/- 7.9 x 10(-5)) compared with BOS-negative patients (1.3 x 10(-5) +/- 2.1 x 10(-6)). CONCLUSIONS: This study indicates that a parallel CD4+ T-cell alloreactivity to both donor HLA Class I and Class II molecules may play a role in the pathogenesis of BOS both in adult and pediatric lung transplant recipients.

Bronchiolitis Obliterans↗

PubMed2001

Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome.

A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS+ and nine BOS-lung transplant recipients were cultured with synthetic peptides corresponding to the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS+ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS- patients (p=0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS+ patients than in BOS- patients (p=0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.

Amino Acid Sequence↗

PubMed2003

T-cell allorecognition and transplant rejection: a summary and update.

Transplant biologists have made significant progress over the last 20 years towards unraveling the immunologic intricacies of allograft rejection. This large body of work has resulted in an improved understanding of T-cell allorecognition at a molecular level and has provided new insight into the functional consequences resulting from the allorecognition events. The findings suggest that the survival and the histologic features of a transplanted organ are influenced not only by the T-cell recognition pathway, but also by the frequency, the induced effector functions and the specific cellular targets of the alloreactive T-cell repertoire.

Animals↗