RESUMO
Tumour-associated antigens (TAAs) comprise a large set of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as targets for immunotherapy has been explored for more than two decades1, yet the origins of TAA-specific T cells remain unclear. While tumour cells may be an important source of TAAs for T cell priming2, several recent studies suggest that infection with some viruses, including Epstein-Barr virus and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs3,4. However, the cellular and molecular basis of such responses remains undefined. Here we show that expression of the Epstein-Barr virus signalling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signalling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on major histocompatibility complex classes I (MHC-I) and II (MHC-II) (mainly through the endogenous pathway) and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in tumour B cells from patients with cancer and thereby enabling them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a wide range of endogenous tumour antigens, such as TAAs and neoantigens, for treating B cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches to treatment of cancers.
Assuntos
Linfócitos B/imunologia , Linfócitos B/virologia , Linfócitos T CD4-Positivos/imunologia , Herpesvirus Humano 4/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Antígenos de Neoplasias/imunologia , Ligante CD27/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Ligante OX40/imunologiaRESUMO
Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.
Assuntos
Antígenos de Histocompatibilidade Classe I , Isoanticorpos , Humanos , Alelos , Teste de Histocompatibilidade/métodos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA/genética , AntígenosRESUMO
ABO compatibility is important for kidney transplantation, with longer waitlist times for blood group B kidney transplant candidates. However, kidneys from non-A1 (eg, A2) subtype donors, which express less A antigen, can be safely transplanted into group B recipients. ABO subtyping is routinely performed using anti-A1 lectin, but DNA-based genotyping is also possible. Here, we compare lectin and genotyping testing. Lectin and genotype subtyping was performed on 554 group A deceased donor samples at 2 transplant laboratories. The findings were supported by 2 additional data sets of 210 group A living kidney donors and 124 samples with unclear lectin testing sent to a reference laboratory. In deceased donors, genotyping found 65% more A2 donors than lectin testing, most with weak lectin reactivity, a finding supported in living donors and samples sent for reference testing. DNA sequencing and flow cytometry showed that the discordances were because of several factors, including transfusion, small variability in A antigen levels, and rare ABO∗A2.06 and ABO∗A2.16 sequences. Although lectin testing is the current standard for transplantation subtyping, genotyping is accurate and could increase A2 kidney transplant opportunities for group B candidates, a difference that should reduce group B wait times and improve transplant equity.
Assuntos
Transplante de Rim , Humanos , Genótipo , Incompatibilidade de Grupos Sanguíneos , Doadores de Tecidos , Doadores Vivos , Sistema ABO de Grupos Sanguíneos/genética , IsoanticorposRESUMO
BACKGROUND: Unproven cellular therapies are being offered to patients for a variety of conditions and diseases for which other treatments have failed. The use of untested cellular therapies is a worldwide problem. Practitioners (e.g., physicians, scientists, QA/QI facility managers, and policy advocates) are perhaps unaware of the risks involved with such therapies. Therefore, a critical need exists to bring attention to the potential limitations and adverse effects of these therapies to inform and limit misinformation. STUDY DESIGN AND METHODS: We describe the extent of the unproven cellular therapy problem through a search of scientific literature and social media coverage. We also describe the regulatory framework that can be used by the practitioner to review and evaluate both proven and unproven cellular therapies. RESULTS: We report on the current state of unproven cellular therapies across the globe. A workflow to facilitate an understanding of the regulatory processes involved in the approval of cellular therapies is provided as well as a list of warnings required by regulatory agencies on various products. It is hoped that this article will serve as a tool kit to educate the practitioner on navigating the field of unproven cellular therapy products. DISCUSSION: Increasing awareness of the issues associated with unproven therapies through education is important to help in reducing misinformation and risks to patients.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Médicos , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , HumanosRESUMO
Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent antitumor immune responses and provide strong motivation for improving our understanding of antigen-T-cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRα and TCRß, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs. We developed a streamlined approach for matching TCR sequences with cognate antigen through on-demand cloning and expression of TCRs and screening against candidate antigens. Here, we first demonstrate the system's capacity to identify viral-antigen-specific TCRs and compare the functional avidity of TCRs specific for a given antigen target. We then apply this system to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs. Furthermore, we use a neoantigen-prediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise to an immunogenic neoantigen mut-MGA, and use this approach to identify the mut-MGA-specific TCR sequence. This approach provides a means to identify and express TCRs, and then rapidly assess antigen specificity and functional avidity of a reconstructed TCR, which can be applied for monitoring antigen-specific T-cell responses, and potentially for guiding the design of effective T-cell-based immunotherapies.
Assuntos
Antígenos de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Vacinas Anticâncer/uso terapêutico , Células Cultivadas , Clonagem Molecular/métodos , Células HEK293 , Humanos , Células Jurkat , Leucemia Linfocítica Crônica de Células B/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4+ T cell responses. XIAP epitope-specific CD4+ T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.
Assuntos
Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/imunologia , Fragmentos de Peptídeos/imunologia , Neoplasias Cutâneas/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia , Proliferação de Células , Células Cultivadas , ELISPOT , Humanos , Imunidade Humoral , Ativação Linfocitária , Melanoma/tratamento farmacológico , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Resultado do TratamentoRESUMO
Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8+ effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1-deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.
Assuntos
Antígeno B7-H1/imunologia , Bronquiolite Obliterante/imunologia , Traqueia/transplante , Imunologia de Transplantes , Animais , Antígeno B7-H1/deficiência , Bronquiolite Obliterante/patologia , Bronquiolite Obliterante/prevenção & controle , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Imunidade Celular , Isoantígenos/imunologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doadores de Tecidos , Traqueia/patologia , Regulação para Cima/imunologiaRESUMO
V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.
Assuntos
Proteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos/administração & dosagem , Antígeno B7-H1/deficiência , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Feminino , Tolerância Imunológica , Ligantes , Ativação Linfocitária , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/deficiência , Receptor de Morte Celular Programada 1/genéticaRESUMO
Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients. High dendritic cell density was associated with poor allograft survival independent of clinical variables. Moreover, high dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. We then explored the association between dendritic cells and histologic variables associated with poor prognosis. Multivariate analysis revealed an independent association between the densities of dendritic cells and T cells. In biopsy samples with high dendritic cell density, electron microscopy showed direct physical contact between infiltrating lymphocytes and cells that have the ultrastructural morphologic characteristics of dendritic cells. The origin of graft dendritic cells was sought in nine sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor dendritic cells predominated initially, the majority of dendritic cells in late allograft biopsy samples were of recipient origin. Our data highlight the prognostic value of dendritic cell density in allograft biopsy samples, suggest a new role for these cells in shaping graft inflammation, and provide a rationale for targeting dendritic cell recruitment to promote long-term allograft survival.
Assuntos
Aloenxertos/patologia , Moléculas de Adesão Celular/análise , Células Dendríticas/química , Sobrevivência de Enxerto , Transplante de Rim , Rim/patologia , Lectinas Tipo C/análise , Receptores de Superfície Celular/análise , Adulto , Aloenxertos/imunologia , Biópsia , Células Dendríticas/patologia , Células Dendríticas/ultraestrutura , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Rim/imunologia , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Nefrite/patologia , Valor Preditivo dos Testes , Linfócitos T/patologia , Linfócitos T/ultraestruturaRESUMO
TIM-3 is constitutively expressed on subsets of macrophages and dendritic cells. Its expression on other cells of the innate immune system and its role in fetomaternal tolerance has not yet been explored. In this study, we investigate the role of TIM-3-expressing innate immune cells in the regulation of tolerance at the fetomaternal interface (FMI) using an allogeneic mouse model of pregnancy. Blockade of TIM-3 results in accumulation of inflammatory granulocytes and macrophages at the uteroplacental interface and upregulation of proinflammatory cytokines. Furthermore, TIM-3 blockade inhibits the phagocytic potential of uterine macrophages resulting in a build up of apoptotic bodies at the uteroplacental interface that elicits a local immune response. In response to inflammatory cytokines, Ly-6C(hi)G(neg) monocytic myeloid-derived suppressor cells expressing inducible NO synthase and arginase 1 are induced. However, these suppressive cells fail to downregulate the inflammatory cascade induced by inflammatory granulocytes (Ly-6C(int)G(hi)) and apoptotic cells; the increased production of IFN-γ and TNF-α by inflammatory granulocytes leads to abrogation of tolerance at the FMI and fetal rejection. These data highlight the interplay between cells of the innate immune system at the FMI and their influence on successful pregnancy in mice.
Assuntos
Tolerância Imunológica , Imunidade Celular , Imunidade Inata , Receptores Virais/fisiologia , Animais , Apoptose/imunologia , Linhagem Celular , Técnicas de Cocultura , Feminino , Receptor Celular 2 do Vírus da Hepatite A , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Gravidez , Receptores Virais/biossíntese , Útero/citologia , Útero/imunologia , Útero/metabolismoRESUMO
RATIONALE: The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. OBJECTIVES: We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation. METHODS: We performed a single-center retrospective cohort study including all patients listed for lung transplantation between January 2008 and August 2012. Per protocol, transplant candidates were assessed by solid phase LABscreen mixed Class I and II and LABscreen Single Antigen assays. MEASUREMENTS AND MAIN RESULTS: Among 224 patients, 34% had anti-HLA antibodies at mean fluorescent intensity (MFI) greater than or equal to 3,000 (group III), and 24% had antibodies at MFI 1,000 to 3,000 (group II). Ninety percent of the patients with pretransplant anti-HLA antibodies had class I antibodies, whereas only seven patients developed class II alone. Patients in group III were less likely to receive transplants than patients without any anti-HLA antibodies (group I) (45.5 vs. 67.7%, P = 0.005). Wait time to transplant was longer in group III than group I, although this difference did not meet statistical significance, and waitlist mortality was similar. Among transplant recipients, antibody-mediated rejection (AMR) was more frequent in group III than in group II (20% vs. 0%, P = 0.01) or group I (6.3%, P = 0.05). CONCLUSIONS: The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA/sangue , Fatores Imunológicos/sangue , Isoanticorpos/sangue , Transplante de Pulmão , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Estudos Retrospectivos , Doadores de Tecidos , Resultado do TratamentoRESUMO
In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-ß1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8(+) T cells) was observed in the anti-B7h-treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8(+) T cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8(+) T cells (in particular, CD8(+)CD103(+) cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8(+) effector response and reducing local immunomodulation mediated by CD8(+) regulatory T cells.
Assuntos
Tolerância Imunológica/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Citocinas/biossíntese , Perda do Embrião/imunologia , Feminino , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/antagonistas & inibidores , Tamanho da Ninhada de Vivíparos/imunologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Gravidez , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplanteRESUMO
Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype and function of pathogenic T cells across the spectrum of severity requires investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, SJS/TEN and DRESS, and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling and scRNAseq + CITEseq + TCRseq supported in SJS/TEN clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin, along with expanded and non-expanded cytotoxic CD8+ skin TRM. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRM as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRM were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced regulatory T cell (Treg) signature compared to MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin like SJS/TEN, yet a pro-Treg signature like MDE. These findings have important implications for fundamental skin immunology and clinical care.
RESUMO
Fetomaternal tolerance has been shown to depend both on regulatory T cells (Tregs) and negative signals from the PD1-PDL1 costimulatory pathway. More recently, IL-17-producing T cells (Th17) have been recognized as a barrier in inducing tolerance in transplantation. In this study, we investigate the mechanisms of PDL1-mediated regulation of fetomaternal tolerance using an alloantigen-specific CD4(+) TCR transgenic mouse model system (ABM-tg mouse). PDL1 blockade led to an increase in embryo resorption and a reduction in litter size. This was associated with a decrease in Tregs, leading to a lower Treg/effector T cell ratio. Moreover, PDL1 blockade inhibited Ag-specific alloreactive T cell apoptosis and induced apoptosis of Tregs and a shift toward higher frequency of Th17 cells, breaking fetomaternal tolerance. These Th17 cells arose predominantly from CD4(+)Foxp3(-) cells, rather than from conversion of Tregs. Locally in the placenta, similar decrease in regulatory and apoptotic markers was observed by real-time PCR. Neutralization of IL-17 abrogated the anti-PDL1 effect on fetal survival rate and restored Treg numbers. Finally, the adoptive transfer of Tregs was also able to improve fetal survival in the setting of PDL1 blockade. This is to our knowledge the first report using an alloantigen-specific model that establishes a link between PDL1, Th17 cells, and fetomaternal tolerance.
Assuntos
Antígeno B7-H1/fisiologia , Antígenos de Histocompatibilidade Classe II/fisiologia , Histocompatibilidade Materno-Fetal/imunologia , Tolerância Imunológica , Interleucina-17/fisiologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Animais , Antígenos de Diferenciação/fisiologia , Antígeno B7-H1/antagonistas & inibidores , Feminino , Técnicas de Introdução de Genes , Antígenos de Histocompatibilidade Classe II/genética , Histocompatibilidade Materno-Fetal/genética , Tolerância Imunológica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Receptor de Morte Celular Programada 1/fisiologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologia , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. Here, we use TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following PD-1 inhibition. The treatment was associated with a sharp increase in circulating alloreactive CD8+ T cell clones, which display a unique transcriptomic signature and were also detected in the rejected kidney but not at tumor sites. Longitudinal and cross-tissue TCR analyses indicate unintended expansion of alloreactive CD8+ T cells induced by ICI therapy for cancer, coinciding with ICI-associated organ rejection.
Assuntos
Linfócitos T CD8-Positivos , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Rim , Rejeição de Enxerto/prevenção & controle , Células Clonais , Receptores de Antígenos de Linfócitos T , AloenxertosRESUMO
Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles CRS after chimeric antigen receptor-T therapy. We conducted this single-center retrospective study to evaluate the association of posthaploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction and was graded according to established criteria. The development of posthaploidentical HCT CRS was associated with a lower incidence of disease relapse (P = .024) but with an increased risk of chronic graft-versus-host disease GVHD (P = .01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor total nucleated cell dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (P < .0005), CD4+ Tcon (P < .005), and CD8+ T cells (P < .005) increased 1 month after HCT compared with those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells 1 month after HCT was most notable among patients with CRS who received a bone marrow graft (P < .005). The development of posthaploidentical HCT CRS is associated with a reduced incidence of disease relapse and a transient effect on post-HCT immune reconstitution of T cells and their subsets. Therefore, the validation of these observations in a multicenter cohort is required.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndrome da Liberação de Citocina/etiologia , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologiaRESUMO
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.
Assuntos
Antígeno B7-1/biossíntese , Tolerância Imunológica , Glicoproteínas de Membrana/biossíntese , Linfócitos T/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/fisiologia , Antígeno B7-H1 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/genética , Células-Tronco Hematopoéticas/metabolismo , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Interferon gama , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Especificidade de Órgãos/imunologia , Peptídeos/deficiência , Peptídeos/genética , Peptídeos/fisiologia , Proteína 2 Ligante de Morte Celular Programada 1 , Linfócitos T/metabolismoRESUMO
The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.
Assuntos
Antígenos de Superfície/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Antígeno B7-1/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/prevenção & controle , Insulina/fisiologia , Glicoproteínas de Membrana/fisiologia , Peptídeos/fisiologia , Transdução de Sinais/fisiologia , Animais , Antígeno B7-H1 , Células Cultivadas , Feminino , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos NOD , Receptor de Morte Celular Programada 1 , Indução de RemissãoRESUMO
Parasitic infections frequently lead to immune deviation or suppression. However, the application of specific parasitic molecules in regulating autoimmune responses remains to be explored. Here we report on the immune modulatory function of Lacto-N-fucopentaose III (LNFPIII), a schistosome glycan, in an animal model for multiple sclerosis. We found that LNFPIII treatment significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE) and CNS inflammation, and skewed peripheral immune response to a Th2 dominant profile. Inflammatory monocytes (IMCs) purified from LNFPIII-treated mice had increased expression of nitric oxide synthase 2, and mediated T cell suppression. LNFPIII treatment also significantly increased mRNA expression of arginase-1, aldehyde dehydrogenase 1 subfamily A2, indoleamine 2,3-dioxygenase and heme oxygenase 1 in splenic IMCs. Furthermore, LNFPIII treatment significantly reduced trafficking of dendritic cells across brain endothelium in vitro. In summary, our study demonstrates that LNFPIII glycan treatment suppresses EAE by modulating both innate and T cell immune response.