RESUMO
Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality.
Assuntos
Cardiopatias , Transplante de Coração , Doenças Vasculares , Humanos , Hematopoiese Clonal/genética , Transplante de Coração/efeitos adversos , Doenças Vasculares/etiologia , Fatores de Risco , AloenxertosRESUMO
Natural antibodies are an integral part of innate humoral immunity yet their development and polyreactive nature are still enigmatic. Here, we show that characteristic monoclonal natural antibodies recognize common chemical moieties or adducts, supporting the view that polyreactive antibodies may often correspond to anti-adduct antibodies. We next examined the development of immunoglobulin M (IgM) and IgG to 81 ubiquitous adducts from birth to old age. Newborn IgM only reacted to a limited number of consensus determinants. This highly restricted neonatal repertoire abruptly diversified around 6 months of age through the development of antibodies to environmental antigens and age-driven epigenetic modifications. In contrast, the IgG repertoire was diverse across the entire life span. Our studies reveal an unrecognized component of humoral immunity directed to common adducts. These findings set the ground for further investigations into the role of anti-adduct B cell responses in homeostatic functions and pathological conditions.
Assuntos
Anticorpos Monoclonais , Antígenos , Recém-Nascido , Lactente , Humanos , Imunoglobulina M , Imunoglobulina GRESUMO
BACKGROUND: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. METHODS: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. RESULTS: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). CONCLUSIONS: The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.
Assuntos
Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Transplante Homólogo , Imunoglobulina G , Antígenos HLA , Aloenxertos , Rejeição de Enxerto , Sobrevivência de EnxertoRESUMO
Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens mismatched between donor and recipient are well-recognized targets of humoral alloimmunity in SOT and thought to drive most cases of AMR. In contrast, the implication of minor histocompatibility antigens (mHAs) in AMR has not been fully investigated, and their clinical relevance remains controversial. Recent technological advances, allowing for genome-wide comparisons between donors and recipients, have uncovered novel, polymorphic mHA targets with potential influence on the graft outcome following SOT. Here, we review these latest studies relating to mHAs and discuss their clinical significance.
Assuntos
Rejeição de Enxerto , Transplante de Órgãos , Formação de Anticorpos , Rejeição de Enxerto/prevenção & controle , Antígenos HLA , Histocompatibilidade , Antígenos de Histocompatibilidade Menor , Transplante de Órgãos/efeitos adversosRESUMO
The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.
Assuntos
Diferenciação Celular , Plasmócitos/citologia , Timo/citologia , Adulto , Antígenos CD/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos B/ultraestrutura , Sangue Fetal/citologia , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Imunoglobulina G/metabolismo , Cadeias Pesadas de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/imunologia , Recém-Nascido , Subpopulações de Linfócitos/citologia , Análise de Componente Principal , RNA-Seq , Análise de Célula Única , Hipermutação Somática de Imunoglobulina/genética , Transcriptoma/genéticaRESUMO
BACKGROUND: The relationship between circulating effector memory T and B cells long after transplantation and their susceptibility to immunosuppression are unknown. To investigate the impact of antirejection therapy on T cell-B cell coordinated immune responses, we assessed IFN-γ-producing memory cells and natural antibodies (nAbs) that potentially bind to autoantigens on the graft. METHODS: Plasma levels of IgG nAbs to malondialdehyde (MDA) were measured in 145 kidney transplant recipients at 5-7 years after transplantation. In 54 of these patients, the number of donor-reactive IFN-γ-producing cells was determined. 35/145 patients experienced rejection, 18 of which occurred within 1 year after transplantation. RESULTS: The number of donor-reactive IFN-γ-producing cells and the levels of nAbs were comparable between rejectors and nonrejectors. The nAbs levels were positively correlated with the number of donor-reactive IFN-γ-producing cells (r s = 0.39, p=0.004). The positive correlation was only observed in rejectors (r s = 0.53, p=0.003; nonrejectors: r s = 0.24, p=0.23). Moreover, we observed that intravenous immune globulin treatment affected the level of nAbs and this effect was found in patients who experienced a late ca-ABMR compared to nonrejectors (p=0.008). CONCLUSION: The positive correlation found between alloreactive T cells and nAbs in rejectors suggests an intricate role for both components of the immune response in the rejection process. Treatment with intravenous immune globulin impacted nAbs.
RESUMO
BACKGROUND: Antibody mediated rejection (AMR) is an increasingly studied cause of graft failure after heart transplantation. AMR diagnosis previously required the detection of circulating donor specific antibodies (DSA); however, the most recent criteria only require pathological findings. This classification defined a subset of patients with AMR, yet without known antibodies. Here, we sought to evaluate differences in the transcriptome profile associated with different types of AMR. METHODS: RNA sequencing was used on endomyocardial biopsies to analyze and compare transcriptomic profiles associated with different subtypes of AMR defined by immunopathological and histopathological findings, as well as the presence or absence of DSA. Gene expression profiles were characterized for each diagnostic group. RESULTS: The most divergent gene expression profiles were observed between patients with or without DSA. AMR subtypes associated with DSA showed expression of signature genes involved in monocyte activation and response to interferon. There was also substantial difference between the transcriptomic profiles of AMR defined by histopathological and immunopathological findings, the latter being associated with expression of mucin genes. In contrast, there was no differential RNA expression between patients with pAMR1i without DSA and those without AMR. Likewise, no differential expression was observed between patients with pAMR1h with DSA and pAMR2. CONCLUSIONS: Overall, our studies reveal different expression profiles in endomyocardial biopsies in relation to some key criteria used to diagnose AMR. These findings support the view that the diagnosis of AMR encompasses several phenotypes that may rely on distinct mechanisms of injury.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Isoanticorpos/imunologia , Miocárdio/patologia , Doadores de Tecidos , Transcriptoma/imunologia , Adolescente , Adulto , Biópsia , Criança , Feminino , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Adulto JovemRESUMO
T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor ß chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFß) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.
Assuntos
Transplante de Coração , Aloenxertos , Vasos Coronários , Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , Humanos , Linfócitos TRESUMO
Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single-center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non-AMR (n = 21) were tested for reactivity against a panel of 44 non-HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non-AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta-tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non-AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.
Assuntos
Formação de Anticorpos , Transplante de Coração , Rejeição de Enxerto/etiologia , Antígenos HLA , Transplante de Coração/efeitos adversos , Humanos , Isoanticorpos , Doadores de Tecidos , VimentinaRESUMO
Antibody-mediated rejection continues to hinder long-term survival of solid organ allografts. Natural antibodies (Nabs) with polyreactive and autoreactive properties have recently emerged as potential contributors to antibody-mediated graft rejection. This review discusses Nabs, their functions in health and disease, their significance in rejection following kidney, heart, and lung transplantation, and their implication in serum reactivity to key antigens associated with rejection. Finally, potential effector mechanisms of Nabs in the context of transplantation are explored.
Assuntos
Anticorpos/imunologia , Autoimunidade , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Órgãos , Sobrevivência de Enxerto , HumanosRESUMO
BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.
Assuntos
Rejeição de Enxerto/imunologia , Hemorragia/imunologia , Imunoglobulina G/sangue , Receptor Tipo 1 de Angiotensina/imunologia , Microangiopatias Trombóticas/imunologia , Vasculite/imunologia , Doença Aguda , Adulto , Idoso , Células Endoteliais/imunologia , Endotelina-1/imunologia , Feminino , Rejeição de Enxerto/patologia , Rejeição de Enxerto/fisiopatologia , Hemorragia/patologia , Humanos , Glomérulos Renais/patologia , Transplante de Rim/efeitos adversos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Microangiopatias Trombóticas/patologia , Fatores de Tempo , Vasculite/patologiaRESUMO
Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens.Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde.Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss.Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.
Assuntos
Aloenxertos/patologia , Rejeição de Enxerto/sangue , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Imunoglobulina G/sangue , Transplante de Rim , Adulto , Aloenxertos/imunologia , Feminino , Antígenos HLA/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Malondialdeído/imunologia , Pessoa de Meia-Idade , Período Pós-Operatório , Período Pré-Operatório , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. METHODS: B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. RESULTS: B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. CONCLUSIONS: Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.
Assuntos
Linfócitos B , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/imunologia , Transplante de Coração , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/imunologia , Adulto , Aloenxertos , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Feminino , Humanos , Imuno-Histoquímica , Macrófagos , Masculino , Pessoa de Meia-Idade , Plasmócitos , Complicações Pós-Operatórias/patologia , Adulto JovemRESUMO
BACKGROUND: Allospecific anti-HLA antibodies (Abs) are associated with rejection of solid organ grafts. The 2 main kits to detect anti-HLA Ab in patient serum are commercialized by Immucor and One Lambda/ThermoFisher. We sought to compare the performance of both platforms. METHODS: Background-adjusted mean fluorescence intensity (MFI) values were used from both platforms to compare sera collected from 125 pretransplant and posttransplant heart and lung transplant recipients. RESULTS: Most HLA class I (94.5%) and HLA class II (89%) Abs with moderate to high MFI titer (≥4000) were detected by both assays. A modest correlation was observed between MFI values obtained from the 2 assays for both class I (r = 0.3, r2 = 0.09, P < 0.0001) and class II Ab (r = 0.707, r2 = 0.5, P < 0.0001). Both assays detected anti-class I and II Ab that the other did not; however, no specific HLA allele was detected preferentially by either of the 2 assays. For a limited number of discrepant sera, dilution resulted in comparable reactivity profiles between the 2 platforms. CONCLUSIONS: Immucor and One Lambda/ThermoFisher assays have a similar, albeit nonidentical, ability to detect anti-HLA Ab. Although the correlation between the assays was present, significant variances exist, some of which can be explained by a dilution-sensitive "prozone" effect.
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BACKGROUND: Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. METHODS: IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. RESULTS: No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). CONCLUSIONS: Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Insuficiência Cardíaca/cirurgia , Transplante de Coração/efeitos adversos , Coração Auxiliar/efeitos adversos , Imunoglobulina G/imunologia , Disfunção Primária do Enxerto/etiologia , Aloenxertos , Angiografia , Anticorpos Anti-Idiotípicos/imunologia , Apoptose , Linfócitos B/imunologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Epitopos , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/diagnóstico , Estudos Retrospectivos , Linfócitos T/imunologiaRESUMO
PURPOSE OF REVIEW: Antibody-mediated rejection (ABMR), especially in its chronic manifestation, is increasingly recognized as a leading cause of late graft loss following solid organ transplantation. In recent years, autoantibodies have emerged as a significant component of the humoral response to allografts alongside anti-human leukocyte antigen antibodies. These include polyreactive antibodies also known as natural antibodies (Nabs) secreted by innate B cells. A hallmark of Nabs is their capacity to bind altered self such as oxidized lipids on apoptotic cells. This review provides an overview of these overlooked antibodies and their implication in the pathophysiology of ABMR. RECENT FINDINGS: New evidence reported in the past few years support a contribution of immunoglobulin (Ig) G Nabs to ABMR. Serum IgG Nabs levels are significantly higher in patients with ABMR compared with control kidney transplant recipients with stable graft function. Pretransplant IgG Nabs are also associated with ABMR and late graft loss. IgG Nabs are almost exclusively of the IgG1 and IgG3 subclasses and have the capacity to activate complement. SUMMARY: In conclusion, Nabs are important elements in host immune responses to solid organ grafts. The recent description of their implication in ABMR and late kidney graft loss warrants further investigation into their pathogenic potential.
Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/métodos , Rim/imunologia , HumanosRESUMO
The ability of recombinant outer membrane proteins of Pasteurella pneumotropica to vaccinate against the infections of mice was studied. The proteins examined were the homologues of the P4, P6, P26, and D15 proteins of Haemophilus influenzae. Intranasal vaccination with P4 and P6 produced protection against pneumonia. P6 vaccination, which was most studied, reduced the peak bacteria load in lungs by 50-fold and caused a rapid resolution of an infection that lasted for at least 5 days in unvaccinated animals. Protection could be partially transferred with CD4(+) T cells and pulmonary challenge with the P6 antigen induced interferon-γ and the Th17 cytokine IL-21. This is the first demonstration of the ability of a recombinant P6 to mediate protective immunity to a pathogen in its natural host and it is proposed that it would not only have utility for mouse breeding but also for investigating how to improve the efficacy of vaccination with homologous proteins for related species.