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1.
Front Immunol ; 15: 1429335, 2024.
Article in English | MEDLINE | ID: mdl-39131162

ABSTRACT

We have previously reported that nanoparticles (NPs) loaded with IL-2 and TGF-ß and targeted to T cells induced polyclonal T regulatory cells (Tregs) that protected mice from graft-versus-host disease (GvHD). Here, we evaluated whether administration of these NPs during alloantigen immunization could prevent allograft rejection by converting immunogenic responses to tolerogenic ones. Using C57BL/6 mice and BALB/c mice as either donors or recipients of allogeneic splenocytes, we found that treatment with the tolerogenic NPs in both strains of mice resulted in a marked inhibition of mixed lymphocyte reaction (MLR) to donor cell alloantigen but not to third-party control mouse cells after transfer of the allogeneic cells. The decreased alloreactivity associated with a four- to fivefold increase in the number of CD4+ and CD8+ T regulatory cells (Tregs) and the acquisition of a tolerogenic phenotype by recipient dendritic cells (DCs) in NP-treated mice. As allogeneic cells persisted in NP-treated mice, these findings suggest that tolerogenic NPs can induce alloantigen-specific Tregs and tolerogenic DCs promoting tolerogenic responses to alloantigen. By inhibiting reactivity to allotransplant, this approach could help reduce the need for immune suppression for the maintenance of allografts.


Subject(s)
Interleukin-2 , Isoantigens , Mice, Inbred BALB C , Mice, Inbred C57BL , Nanoparticles , T-Lymphocytes, Regulatory , Transforming Growth Factor beta , Transplantation Tolerance , Animals , Isoantigens/immunology , Transplantation Tolerance/immunology , Mice , Transforming Growth Factor beta/immunology , T-Lymphocytes, Regulatory/immunology , Interleukin-2/immunology , Dendritic Cells/immunology , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Female
2.
Front Immunol ; 15: 1418539, 2024.
Article in English | MEDLINE | ID: mdl-39131159

ABSTRACT

CD177 plays an important role in the proliferation and differentiation of myeloid lineage cells including neutrophils, myelocytes, promyelocytes, megakaryocytes, and early erythroblasts in bone marrow. CD177 deficiency is a common phenotype in humans. Our previous studies revealed genetic mechanisms of human CD177 deficiency and expression variations. Up to now, immune functions of CD177 remain undefined. In the current study, we revealed human IgG as a ligand for CD177 by using flow cytometry, bead-rosette formation, and surface plasmon resonance (SPR) assays. In addition, we show that CD177 variants affect the binding capacity of CD177 for human IgG. Furthermore, we show that the CD177 genetic variants significantly affect antibody-dependent cell-mediated cytotoxicity (ADCC) function. The demonstration of CD177 as a functional IgG Fc-receptor may provide new insights into CD177 immune function and genetic mechanism underlying CD177 as biomarkers for human diseases.


Subject(s)
GPI-Linked Proteins , Immunoglobulin G , Humans , Immunoglobulin G/immunology , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/immunology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/immunology , Antibody-Dependent Cell Cytotoxicity , Receptors, IgG/genetics , Receptors, IgG/metabolism , Isoantigens/immunology , Isoantigens/genetics , Genetic Variation , Receptors, Fc/metabolism , Receptors, Fc/genetics , Protein Binding
3.
Front Immunol ; 15: 1367230, 2024.
Article in English | MEDLINE | ID: mdl-38919617

ABSTRACT

The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and functional heterogeneity of MDSCs in newborns remain elusive, hampering the understanding of the importance of MDSCs in neonates. In this study, we unraveled the maturation trajectory of polymorphonuclear (PMN)-MDSCs from the peripheral blood of human newborns by performing single-cell RNA sequencing. Results indicated that neonatal PMN-MDSCs differentiated from self-renewal progenitors, antimicrobial PMN-MDSCs, and immunosuppressive PMN-MDSCs to late PMN-MDSCs with reduced antimicrobial capacity. We also established a simple framework to distinguish these distinct stages by CD177 and CXCR2. Importantly, preterm newborns displayed a reduced abundance of classical PMN-MDSCs but increased late PMN-MDSCs, consistent with their higher susceptibility to infections and inflammation. Furthermore, newborn PMN-MDSCs were distinct from those from cancer patients, which displayed minimum expression of genes about antimicrobial capacity. This study indicates that the heterogeneity of PMN-MDSCs is associated with the maturity of human newborns.


Subject(s)
Gene Expression Profiling , Myeloid-Derived Suppressor Cells , Receptors, Interleukin-8B , Single-Cell Analysis , Transcriptome , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Infant, Newborn , Receptors, Interleukin-8B/metabolism , Receptors, Interleukin-8B/genetics , Neutrophils/immunology , Neutrophils/metabolism , GPI-Linked Proteins/genetics , Cell Differentiation , Female , Male , Isoantigens , Receptors, Cell Surface
4.
J Clin Invest ; 134(11)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38828727

ABSTRACT

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.


Subject(s)
Calcineurin Inhibitors , Graft vs Host Disease , Isoantigens , Memory T Cells , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Graft vs Host Disease/pathology , Animals , Mice , Isoantigens/immunology , Calcineurin Inhibitors/pharmacology , Chronic Disease , Memory T Cells/immunology , Tacrolimus/pharmacology , CD4-Positive T-Lymphocytes/immunology , Cyclosporine/pharmacology , Female , CD8-Positive T-Lymphocytes/immunology , T-Lymphocyte Subsets/immunology
6.
Front Immunol ; 15: 1366125, 2024.
Article in English | MEDLINE | ID: mdl-38715615

ABSTRACT

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.


Subject(s)
Erythema Nodosum , Gene Expression Profiling , Leprosy, Lepromatous , Neutrophil Activation , Neutrophils , Transcriptome , Humans , Erythema Nodosum/immunology , Erythema Nodosum/blood , Leprosy, Lepromatous/immunology , Leprosy, Lepromatous/diagnosis , Leprosy, Lepromatous/blood , Adult , Male , Neutrophils/immunology , Neutrophils/metabolism , Female , Middle Aged , GPI-Linked Proteins/genetics , Thalidomide , Receptors, Cell Surface/genetics , Leprostatic Agents/therapeutic use , Leprostatic Agents/pharmacology , Young Adult , Biomarkers , Isoantigens
7.
Int J Mol Sci ; 25(7)2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38612464

ABSTRACT

Immunodominant alloantigens in pig sperm membranes include 15 known gene products and a previously undiscovered Mr 20,000 sperm membrane-specific protein (SMA20). Here we characterize SMA20 and identify it as the unannotated pig ortholog of PMIS2. A composite SMA20 cDNA encoded a 126 amino acid polypeptide comprising two predicted transmembrane segments and an N-terminal alanine- and proline (AP)-rich region with no apparent signal peptide. The Northern blots showed that the composite SMA20 cDNA was derived from a 1.1 kb testis-specific transcript. A BLASTp search retrieved no SMA20 match from the pig genome, but it did retrieve a 99% match to the Pmis2 gene product in warthog. Sequence identity to predicted PMIS2 orthologs from other placental mammals ranged from no more than 80% overall in Cetartiodactyla to less than 60% in Primates, with the AP-rich region showing the highest divergence, including, in the extreme, its absence in most rodents, including the mouse. SMA20 immunoreactivity localized to the acrosome/apical head of methanol-fixed boar spermatozoa but not live, motile cells. Ultrastructurally, the SMA20 AP-rich domain immunolocalized to the inner leaflet of the plasma membrane, the outer acrosomal membrane, and the acrosomal contents of ejaculated spermatozoa. Gene name search failed to retrieve annotated Pmis2 from most mammalian genomes. Nevertheless, individual pairwise interrogation of loci spanning Atp4a-Haus5 identified Pmis2 in all placental mammals, but not in marsupials or monotremes. We conclude that the gene encoding sperm-specific SMA20/PMIS2 arose de novo in Eutheria after divergence from Metatheria, whereupon rapid molecular evolution likely drove the acquisition of a species-divergent function unique to fertilization in placental mammals.


Subject(s)
Placenta , Semen , Male , Female , Pregnancy , Swine , Animals , Mice , DNA, Complementary , Spermatozoa , Eutheria , Alanine , Isoantigens/genetics , Fertilization/genetics
8.
J Immunol ; 212(12): 1891-1903, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38683146

ABSTRACT

Foxp3+ T regulatory (Treg) cells prevent allograft rejection and graft-versus-host disease. Although polyclonal Tregs have been used both in animal models and in humans, the fine specificity of their suppressive function is poorly defined. We have generated mouse recipient-derived alloantigen-specific Tregs in vitro and explored the fine specificity of their suppressive function and their mechanism of action in vitro and in vivo. In vitro, when alloantigen and peptide Ag were both presented on the same dendritic cell, both responses were suppressed by iTregs specific either for the alloantigen or for the peptide Ag. In vivo, iTreg suppression was limited to the cognate Ag, and no bystander suppression was observed when both allo-antigen and peptide Ag were present on the same dendritic cell. In vitro, alloantigen-specific Tregs captured cognate MHC but failed to capture noncognate MHC. Our results demonstrate that a polyclonal population of iTregs generated from naive T cells can mediate highly specific function in vivo and support the view that Treg therapy, even with unselected polyclonal populations, is likely to be target antigen-specific and that bystander responses to self-antigens or to infectious agents are unlikely.


Subject(s)
Dendritic Cells , Histocompatibility Antigens Class II , Isoantigens , T-Lymphocytes, Regulatory , Animals , Mice , T-Lymphocytes, Regulatory/immunology , Dendritic Cells/immunology , Isoantigens/immunology , Histocompatibility Antigens Class II/immunology , Mice, Inbred C57BL , Mice, Inbred BALB C , Antigen Presentation/immunology , Mice, Transgenic
9.
Oncoimmunology ; 13(1): 2327692, 2024.
Article in English | MEDLINE | ID: mdl-38516269

ABSTRACT

Regulatory T (Treg) cells are critical in shaping an immunosuppressive microenvironment to favor tumor progression and resistance to therapies. However, the heterogeneity and function of Treg cells in esophageal squamous cell carcinoma (ESCC) remain underexplored. We identified CD177 as a tumor-infiltrating Treg cell marker in ESCC. Interestingly, expression levels of CD177 and PD-1 were mutually exclusive in tumor Treg cells. CD177+ Treg cells expressed high levels of IL35, in association with CD8+ T cell exhaustion, whereas PD-1+ Treg cells expressed high levels of IL10. Pan-cancer analysis revealed that CD177+ Treg cells display increased clonal expansion compared to PD-1+ and double-negative (DN) Treg cells, and CD177+ and PD-1+ Treg cells develop from the same DN Treg cell origin. Importantly, we found CD177+ Treg cell infiltration to be associated with poor overall survival and poor response to anti-PD-1 immunotherapy plus chemotherapy in ESCC patients. Finally, we found that lymphatic endothelial cells are associated with CD177+ Treg cell accumulation in ESCC tumors, which are also decreased after anti-PD-1 immunotherapy plus chemotherapy. Our work identifies CD177+ Treg cell as a tumor-specific Treg cell subset and highlights their potential value as a prognostic marker of survival and response to immunotherapy and a therapeutic target in ESCC.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Squamous Cell Carcinoma/pathology , T-Lymphocytes, Regulatory/metabolism , Esophageal Neoplasms/therapy , Programmed Cell Death 1 Receptor , Endothelial Cells/metabolism , Endothelial Cells/pathology , Prognosis , Biomarkers, Tumor , Tumor Microenvironment , Isoantigens , Receptors, Cell Surface , GPI-Linked Proteins
10.
Int J Mol Sci ; 25(5)2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38474126

ABSTRACT

CD177 is a glycosyl phosphatidyl inositol (GPI)-linked, neutrophil-specific glycoprotein that in 3-5% of normal individuals is absent from all neutrophils. The molecular mechanism behind the absence of CD177 has not been unravelled completely. Here, we analyse the impact of the recently described CD177 c.1291G>A variant on CD177 expression. Recombinant CD177 c.1291G>A was expressed in HEK293F cells and its expression on the cell surface, inside the cell, and in the culture supernatant was investigated. The CD177 c.1291G>A protein was characterised serologically and its interaction with proteinase 3 (PR3) was demonstrated by confocal laser scanning microscopy. Our experiments show that CD177 c.1291G>A does not interfere with CD177 protein biosynthesis but affects the membrane expression of CD177, leading to very low copy numbers of the protein on the cellular surface. The mutation does not interfere with the ability of the protein to bind PR3 or human polyclonal antibodies against wild-type CD177. Carriers of the c.1291G>A allele are supposed to be phenotyped as CD177-negative, but the protein is present in soluble form. The presence of CD177 c.1291A leads to the production of an unstable CD177 protein and an apparent "CD177-null" phenotype.


Subject(s)
Isoantigens , Receptors, Cell Surface , Humans , Receptors, Cell Surface/metabolism , GPI-Linked Proteins/metabolism , Alleles , Cell Membrane/metabolism , Myeloblastin/genetics , Phenotype , Isoantigens/genetics , Neutrophils/metabolism
11.
Transfusion ; 64(5): 906-918, 2024 May.
Article in English | MEDLINE | ID: mdl-38530740

ABSTRACT

BACKGROUND: To identify specific human neutrophil antigen (HNA) antibodies, assays using neutrophils such as monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA) are recommended. However, these assays are limited by labor-intensive neutrophil preparation and varying antigen expression levels. METHODS: We evaluated a newly developed immunocomplex capture fluorescence assay (ICFA) for identifying HNA-1 antibodies and compared it to MAIGA and LABScreen Multi (LABM), which utilizes recombinant HNA-coated Luminex beads. For ICFA, HNA-1a or HNA-1b transfected cells replaced neutrophils. Cells incubated with serum were lysed, and immune complexes were captured using five CD16 monoclonal antibody-conjugated Luminex beads. Nine antisera with known specificity and 26 samples suspected of containing HNA antibodies were analyzed by ICFA and MAIGA using neutrophils or transfected cells (ICFA-N or ICFA-T, and MAIGA-N or MAIGA-T, respectively). RESULTS: ICFA-T and MAIGA-N accurately determined the specificity of all antibodies in the nine antiserum samples. The ICFA-T detection limit was 2048-fold for anti-HNA-1a and 256-fold for anti-HNA-1b; the limits of MAIGA-T, MAIGA-N, and LABM were 32-, 4 ~ 64-, and 128-fold for anti-HNA-1a and 64-, 16 ~ 64-, and 32-fold for anti-HNA-1b, respectively. Twelve and 7 of the remaining 26 samples tested negative and positive, respectively, in both ICFA-T and MAIGA-N. Antibody specificity against HNA-1a or HNA-1b determined using ICFA-T agreed with that determined using MAIGA-N and LABM. Another seven samples tested positive in ICFA-T but negative in MAIGA-N. CONCLUSION: The novel ICFA is highly sensitive and exhibits specificity similar to MAIGA and LABM for detecting HNA-1 antibodies.


Subject(s)
Immunoassay , Isoantigens , Neutrophils , Humans , Antibodies, Monoclonal/immunology , Isoantigens/chemistry , Isoantigens/immunology , Neutrophils/immunology , Transfection , Fluorescent Dyes/chemistry , Immunoassay/methods
12.
Transpl Immunol ; 84: 102035, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38518826

ABSTRACT

Overcoming immunological rejection remains a barrier to the safe adoption of Vascularised Composite Allotransplantation (VCA). To mitigate this risk, clinical protocols have been derived from solid organ transplantation, targeting recipient immunomodulation, yet VCA is unique. Face and hand composite allografts are composed of multiple different tissues, each with their own immunological properties. Experimental work suggests that allografts carry variable numbers and populations of donor leukocytes in an organ specific manner. Ordinarily, these passenger leukocytes are transferred from the donor graft into the recipient circulation after transplantation. Whether alloantigen presentation manifests as acute allograft rejection or transplant tolerance is unknown. This review aims to characterise the immunological properties of the constituent parts of the donor face and hand, the potential fate of donor leukocytes and to consider theoretical graft specific interventions to mitigate early rejection.


Subject(s)
Facial Transplantation , Graft Rejection , Hand Transplantation , Vascularized Composite Allotransplantation , Humans , Graft Rejection/immunology , Animals , Transplantation Tolerance , Allografts/immunology , Tissue Donors , Leukocytes/immunology , Isoantigens/immunology , Transplantation, Homologous , Composite Tissue Allografts/immunology
13.
Biomol Biomed ; 24(4): 798-812, 2024 Jan 13.
Article in English | MEDLINE | ID: mdl-38226808

ABSTRACT

Neutrophils are important inflammatory effector cells that protect against foreign invasion but also cause self-harm. Numerous neutrophils infiltrate the lungs in acute respiratory distress syndrome/acute lung injury (ARDS/ALI) patients. However, the exact impact of neutrophil infiltration on ARDS's onset and progression remains unclear. To investigate this, we analyzed two ARDS-related datasets from the Gene Expression Omnibus public database and discovered an association between CD177, a neutrophil-specific surface protein, and ARDS progression. We used quantitative flow cytometry to assess CD177+ neutrophils in the peripheral blood of clinical ARDS patients vs healthy controls, finding a significant increase in CD177+ neutrophils percentage among total neutrophils in ARDS patients. This finding was further confirmed in ALI mouse models. Subsequent animal experiments showed that anti-CD177 effectively reduces pulmonary edema, neutrophil infiltration, and inflammatory cytokine release, along with a decrease in reactive oxygen species (ROS) and myeloperoxidase (MPO) levels. We also established an in vitro co-culture system to mimic neutrophil and lung epithelial cell interactions. In the anti-CD177 group, we observed decreased expression of NLRP3, caspase 1, peptidyl arginine deiminase (PAD4), MPO, and ROS, along with a reduction in certain inflammatory cytokines. These results indicate a crucial role for the CD177 gene in ARDS's development and progression. Inhibiting CD177 may help mitigate excessive activation of NLRP3 inflammasomes, ROS, and neutrophil extracellular traps (NETs), thus alleviating ARDS.


Subject(s)
Acute Lung Injury , Extracellular Traps , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Neutrophils , Respiratory Distress Syndrome , Neutrophils/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Extracellular Traps/metabolism , Animals , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/immunology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Humans , Mice , Inflammasomes/metabolism , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/genetics , Male , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Mice, Inbred C57BL , Isoantigens , Disease Models, Animal , Reactive Oxygen Species/metabolism , Female
14.
Am J Transplant ; 24(6): 933-943, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38228228

ABSTRACT

Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high-affinity clones. This phenomenon, termed "avidity maturation," results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of 2 skin graft-reactive CD8+ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T cell receptor affinity-based competition for cognate antigen. Our data revealed "interclonal CD8-CD8 help," whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an interleukin-2/CD25-dependent manner. Consequently, the CD8-helped high-affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low-affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high-affinity CD8+ T cells can leverage help from low-affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.


Subject(s)
CD8-Positive T-Lymphocytes , Graft Rejection , Mice, Inbred C57BL , Skin Transplantation , Animals , CD8-Positive T-Lymphocytes/immunology , Mice , Graft Rejection/immunology , Isoantigens/immunology , Mice, Transgenic , Mice, Inbred BALB C , Graft Survival/immunology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/genetics
15.
Adv Drug Deliv Rev ; 206: 115179, 2024 03.
Article in English | MEDLINE | ID: mdl-38286164

ABSTRACT

Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in the destruction of insulin-secreting ß cells of the islets of Langerhans. Allogeneic islet transplantation could be a successful treatment for T1DM; however, it is limited by the need for effective, permanent immunosuppression to prevent graft rejection. Upon transplantation, islets are rejected through non-specific, alloantigen specific, and recurring autoimmune pathways. Immunosuppressive agents used for islet transplantation are generally successful in inhibiting alloantigen rejection, but they are suboptimal in hindering non-specific and autoimmune pathways. In this review, we summarize the challenges with cellular immunological rejection and therapeutics used for islet transplantation. We highlight agents that target these three immune rejection pathways and how to package them for controlled, local delivery via biomaterials. Exploring macro-, micro-, and nano-scale immunomodulatory biomaterial platforms, we summarize their advantages, challenges, and future directions. We hypothesize that understanding their key features will help identify effective platforms to prevent islet graft rejection. Outcomes can further be translated to other cellular therapies beyond T1DM.


Subject(s)
Autoimmune Diseases , Diabetes Mellitus, Type 1 , Islets of Langerhans Transplantation , Humans , Diabetes Mellitus, Type 1/drug therapy , Immunosuppressive Agents , Isoantigens , Graft Rejection/prevention & control
16.
Transplantation ; 108(1): 137-147, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37271872

ABSTRACT

Memory T cells that are specific for alloantigen can arise from a variety of stimuli, ranging from direct allogeneic sensitization from prior transplantation, blood transfusion, or pregnancy to the elicitation of pathogen-specific T cells that are cross-reactive with alloantigen. Regardless of the mechanism by which they arise, alloreactive memory T cells possess key metabolic, phenotypic, and functional properties that render them distinct from naive T cells. These properties affect the immune response to transplantation in 2 important ways: first, they can alter the speed, location, and effector mechanisms with which alloreactive T cells mediate allograft rejection, and second, they can alter T-cell susceptibility to immunosuppression. In this review, we discuss recent developments in understanding these properties of memory T cells and their implications for transplantation.


Subject(s)
Graft Rejection , Memory T Cells , Graft Rejection/prevention & control , Transplantation, Homologous , Skin Transplantation , Isoantigens , Immunologic Memory
17.
Front Immunol ; 14: 1287546, 2023.
Article in English | MEDLINE | ID: mdl-38143762

ABSTRACT

Introduction: Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed. Methods: Here, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8+ T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens. Results: Strikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8+ T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer+ CD8+ T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8+ T cells that were GFP+ was <1%. These data show that a significant percentage of viral-specific memory CD8+ T cells expressed T cell receptors that also recognized alloantigens in vivo. Notably, the frequency of cross-reactive CD8+ T cells differed depending upon the viral epitope. Further, TCR sequences derived from cross-reactive T cells harbored distinctive motifs that may provide insight into cross-reactivity and allo-specificity. Discussion: In sum, we have established a mouse model to track viral-specific, allo-specific, and cross-reactive T cells; revealing that prior infection elicits substantial numbers of viral-specific T cells that cross-react to alloantigen, respond very early after transplant, and may promote rapid rejection.


Subject(s)
CD8-Positive T-Lymphocytes , Virus Diseases , Mice , Animals , Mice, Inbred C57BL , Lymphocytic choriomeningitis virus , Receptors, Antigen, T-Cell/genetics , Isoantigens , Allografts
18.
Int J Immunogenet ; 50 Suppl 2: 3-63, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37919251

ABSTRACT

Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.


Subject(s)
Isoantibodies , Organ Transplantation , Humans , Organ Transplantation/adverse effects , Histocompatibility Testing , Isoantigens , United Kingdom , HLA Antigens , Graft Rejection
19.
Transpl Immunol ; 81: 101951, 2023 12.
Article in English | MEDLINE | ID: mdl-37939887

ABSTRACT

BACKGROUND: During allogeneic Hematopoietic stem cell transplantation (HSCT), frequent pathological scenarios include graft versus host disease (GVHD) and viral infections. We hypothesized if exogenous stimulus as alloantigen and viral antigens might impact on central and effector memory T cells in pediatric recipients. PATIENTS AND METHODS: Subjects included 21 pediatric recipients and 20 healthy children (control group). Peripheral blood samples of patients were collected along the first 712 days post-HSCT. T cell phenotyping of naïve, central, and effector memory T cells (TCMs and TEMs, respectively) was conducted using flow cytometry. Viral nucleic acids were detected using real-time PCR. RESULTS: T cell reconstitution was not reached after 1 year post-HSCT. Chronic GVHD was associated with increased numbers of naïve CD4 T cells (p < 0.05) as well as an increase in TEM and TCM cells of the CD4 (p < 0.0001 and p < 0.05, respectively) and CD8 T cell TEM (p < 0.0001). and TCM (p < 0.001) populations too. Moreover, BK and Epstein-Barr viruses were the main viral pathogens detected (<104 copies), which were associated with a decrease in all T cell compartments. CONCLUSION: During chronic GVHD, alloantigen persistence generates TEM cell enrichment among CD4 and CD8 T cells, and viral infections are associated with deficient recovery of T cells after HSCT.


Subject(s)
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Virus Diseases , Humans , Child , Memory T Cells , CD8-Positive T-Lymphocytes , Isoantigens
20.
Transfusion ; 63(12): 2282-2288, 2023 12.
Article in English | MEDLINE | ID: mdl-37952222

ABSTRACT

BACKGROUND: Antibodies against human neutrophil antigen (HNA) are involved in the pathogenesis of neonatal alloimmune neutropenia, autoimmune neutropenia, and transfusion-related acute lung injury. The present methods for anti-HNA antibody identification strongly depend on the presence of standard antisera with known allo/isospecificities. Here, we aimed to produce recombinant humanized antibodies to HNA from available mouse monoclonal antibodies (MoAbs). STUDY DESIGN AND METHODS: RNAs were extracted from available hybridoma cells producing mouse anti-HNA antibodies recognizing HNA-1a (TAG-1), -1b (TAG-2), -2 (TAG-4), and FcγRIIIb, and the cDNA was synthesized. Recombinant fragments consisting of the variable regions of the H and L chains of the mouse MoAb ligated to the constant region of human IgG were incorporated into an expression vector and transfected into CHO cells. Antibody specificity of the selected humanized monoclonal antibodies was confirmed, and tested by the participants of the ISBT Granulocyte Immunobiology Working Party (GIWP) workshop 2020. RESULTS: GIFT results confirmed the specific reactivity of TAGH-1 to -4, except for a cross-reactivity of TAGH-2 with HNA-1a/a neutrophils, only in flow-cytometry. MAIGA results showed clear specificity of all humanized antibodies, but the selection of the appropriate capture monoclonal antibody was essential for the test. The results of the ISBT GIWP showed high concordance among the labs. CONCLUSIONS: These are the first humanized monoclonal antibodies to HNA-1 and HNA-2 antigens produced and they will be important standard reagents for laboratories testing for neutrophil antibodies. We plan to have these humanized MoAbs available through WHO.


Subject(s)
Neutropenia , Neutrophils , Infant, Newborn , Cricetinae , Humans , Animals , Mice , Cricetulus , Isoantigens , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized
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