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1.
Ann Surg ; 278(6): 873-882, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37051915

RESUMO

OBJECTIVES: To characterize and quantify accumulating immunologic alterations, pre and postoperatively in patients undergoing elective surgical procedures. BACKGROUND: Elective surgery is an anticipatable, controlled human injury. Although the human response to injury is generally stereotyped, individual variability exists. This makes surgical outcomes less predictable, even after standardized procedures, and may provoke complications in patients unable to compensate for their injury. One potential source of variation is found in immune cell maturation, with phenotypic changes dependent on an individual's unique, lifelong response to environmental antigens. METHODS: We enrolled 248 patients in a prospective trial facilitating comprehensive biospecimen and clinical data collection in patients scheduled to undergo elective surgery. Peripheral blood was collected preoperatively, and immediately on return to the postanesthesia care unit. Postoperative complications that occurred within 30 days after surgery were captured. RESULTS: As this was an elective surgical cohort, outcomes were generally favorable. With a median follow-up of 6 months, the overall survival at 30 days was 100%. However, 20.5% of the cohort experienced a postoperative complication (infection, readmission, or system dysfunction). We identified substantial heterogeneity of immune senescence and terminal differentiation phenotypes in surgical patients. More importantly, phenotypes indicating increased T-cell maturation and senescence were associated with postoperative complications and were evident preoperatively. CONCLUSIONS: The baseline immune repertoire may define an immune signature of resilience to surgical injury and help predict risk for surgical complications.


Assuntos
Procedimentos Cirúrgicos Eletivos , Complicações Pós-Operatórias , Humanos , Estudos Prospectivos , Procedimentos Cirúrgicos Eletivos/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Readmissão do Paciente , Coleta de Dados
2.
J Immunol ; 206(7): 1668-1676, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33597150

RESUMO

Costimulation blockade (CoB)-based immunosuppression offers the promise of improved transplantation outcomes with reduced drug toxicity. However, it is hampered by early acute rejections, mediated at least in part by differentiated, CoB-resistant T cells, such as CD57+PD1- CD4 T cells. In this study, we characterize these cells pretransplant, determine their fate posttransplant, and examine their proliferative capacity in vitro in humans. Our studies show that CD57+PD1- CD4 T cells are correlated with increasing age and CMV infection pretransplant, and persist for up to 1 y posttransplant. These cells are replication incompetent alone but proliferated in the presence of unsorted PBMCs in a contact-independent manner. When stimulated, cells sorted by CD57/PD1 status upregulate markers of activation with proliferation. Up to 85% of CD57+PD1- cells change expression of CD57/PD1 with stimulation, typically, upregulating PD1 and downregulating CD57. PD1 upregulation is accentuated in the presence of rapamycin but prevented by tacrolimus. These data support a general theory of CoB-resistant cells as Ag-experienced, costimulation-independent cells and suggest a mechanism for the synergy of belatacept and rapamycin, with increased expression of the activation marker PD1 potentiating exhaustion of CoB-resistant cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Rejeição de Enxerto/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Receptor de Morte Celular Programada 1/metabolismo , Abatacepte/uso terapêutico , Adulto , Antígenos CD57/metabolismo , Plasticidade Celular , Infecções por Citomegalovirus/tratamento farmacológico , Sinergismo Farmacológico , Feminino , Regulação da Expressão Gênica , Rejeição de Enxerto/tratamento farmacológico , Humanos , Terapia de Imunossupressão , Imunossupressores , Falência Renal Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/genética , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico
3.
Ann Surg ; 275(6): 1094-1102, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35258509

RESUMO

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.


Assuntos
Biologia Computacional , Proteômica , Genômica , Humanos , Metabolômica , Estudos Prospectivos , Proteômica/métodos
4.
Pediatr Transplant ; 26(8): e14371, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35938682

RESUMO

BACKGROUND: Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre-transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post-transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study. METHODS: Ninety-eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition-based pre-transplant measurements. Incidence of infectious and alloimmune outcomes at 1-year post-transplantation was compared between nutritional groups using Gray's test and Fine-Gray subdistribution hazards model. Event-free survival was estimated by Kaplan-Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements. RESULTS: We did not observe that nutritional status was associated with infectious or alloimmune events or event-free survival post-transplant. We demonstrated that children with obesity had distinct T-and B-cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9-month post-transplant (p < .001), a higher frequency of CD4 CD57 + PD1- T cells, and lower frequencies of CD57-PD1+ CD8 and CD57-PD1- CD8 T cells at 12-month transplant (p < .05 for all). CONCLUSIONS: Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression.


Assuntos
Transplante de Rim , Desnutrição , Humanos , Terapia de Imunossupressão , Linfócitos T CD8-Positivos , Desnutrição/complicações , Obesidade
5.
Am J Transplant ; 21(2): 766-775, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33480466

RESUMO

Depletional induction using antithymocyte globulin (ATG) reduces rates of acute rejection in adult kidney transplant recipients, yet little is known about its effects in children. Using a longitudinal cohort of 103 patients in the Immune Development in Pediatric Transplant (IMPACT) study, we compared T cell phenotypes after ATG or non-ATG induction. We examined the effects of ATG on the early clinical outcomes of alloimmune events (development of de novo donor specific antibody and/or biopsy proven rejection) and infection events (viremia/viral infections). Long-term patient and graft outcomes were examined using the Scientific Registry of Transplant Recipients. After ATG induction, although absolute counts of CD4 and CD8 T cells were lower, patients had higher percentages of CD4 and CD8 memory T cells with a concomitant decrease in frequency of naïve T cells compared to non-ATG induction. In adjusted and unadjusted models, ATG induction was associated with increased early event-free survival, with no difference in long-term patient or allograft survival. Decreased CD4+ naïve and increased CD4+ effector memory T cell frequencies were associated with improved clinical outcomes. Though immunologic parameters are drastically altered with ATG induction, long-term clinical benefits remain unclear in pediatric patients.


Assuntos
Soro Antilinfocitário , Transplante de Rim , Adulto , Soro Antilinfocitário/uso terapêutico , Criança , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Imunossupressores , Transplante de Rim/efeitos adversos , Fenótipo
6.
Hepatology ; 72(2): 569-583, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31721246

RESUMO

BACKGROUND AND AIMS: As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS: We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSIONS: This study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.


Assuntos
Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Transplante de Fígado , Sirolimo/uso terapêutico , Tolerância ao Transplante , Suspensão de Tratamento , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
7.
Transpl Int ; 34(3): 572-584, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453073

RESUMO

Vascularized composite allotransplants (VCAs) seem to have several unique features of clinical and experimental importance, including uniquely definable lymphatic drainage that can be easily accessed at the level of ipsilateral regional node beds. Thus, VCA offers a unique opportunity to assess the relative contribution of peripheral and secondary lymphoid tissue to the process of rejection. We transplanted hind limb grafts from C3H donors to six different groups of C57BL/6 recipients: Spleen+ Map3k14-/- ; Spleen- Map3k14-/- ; Spleen+ Node- Map3k14-/- ; and Spleen- Node- Map3k14-/- . As positive controls, we used Map3k14+/- with or without spleen. Map3k14+/- mice demonstrated an average graft survival of 9.6 and 9.2 days for Spleen- and Spleen+ Map3k14+/- , respectively. Rejection in the Map3k14-/- group was considerably delayed (28.4 days, P = 0.002) in all recipients. The Spleen- Map3k14-/- mice rejected their hind limb allografts in an even more delayed fashion compared to Spleen+ Map3k14-/- (54.4 days, P = 0.02). Histological analysis of skin showed that acute rejection in both Map3k14+/- mice groups was graded as Banff III or Banff IV. In the Map3k14-/- groups, rejection was graded as Banff III. We demonstrated that in the absence of lymph nodes, grafts reject in a delayed fashion. Also, splenectomy in alymphoplastic mice further extends graft survival, but does not eliminate rejection all together.


Assuntos
Rejeição de Enxerto , Alotransplante de Tecidos Compostos Vascularizados , Aloenxertos , Animais , Sobrevivência de Enxerto , Imunossupressores , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL
8.
Transpl Int ; 33(10): 1294-1301, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277724

RESUMO

Vascularized composite allotransplantation (VCA) is challenged by the morbidity of immunosuppression required to prevent rejection. The use of highly specific biologics has not been well explored in VCA. Given that psoriasis is T-cell mediated, as is rejection of skin-containing VCAs, we sought to assess the role of ustekinumab and secukinumab, which are approved to treat psoriasis by inhibiting Th17 cells. We combined these agents with belatacept and steroids in a VCA nonhuman primate model. Group I consisted of belatacept and steroids, group II was belatacept, ustekinumab with steroid taper, and group III was belatacept, secukinumab with steroid taper. Three animals were transplanted in each group. In group I, the mean graft survival time until the first sign of rejection was 10 days whereas in group II and III it was 10.33 and 11 days, respectively. The immunohistochemistry analysis showed that the number of IL-17a+ cells and the intensity of IL-17a expression were significantly reduced in both dermis and hypodermis parts in groups II and III when compared to group I (P < 0.01). Ustekinumab and secukinumab led to less T-cell infiltration and IL-17a expression in the allograft but provided no benefit to belatacept and steroids in VCA survival.


Assuntos
Sobrevivência de Enxerto , Alotransplante de Tecidos Compostos Vascularizados , Animais , Rejeição de Enxerto/prevenção & controle , Imunossupressores , Primatas , Células Th17
9.
Clin Immunol ; 191: 10-20, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518577

RESUMO

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal.


Assuntos
Inibidores de Janus Quinases/farmacologia , Leucócitos/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Feminino , Voluntários Saudáveis , Humanos , Leucócitos/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
10.
J Am Soc Nephrol ; 28(1): 359-367, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27413076

RESUMO

An individual's immune function, susceptibility to infection, and response to immunosuppressive therapy are influenced in part by his/her T cell maturation state. Although childhood is the most dynamic period of immune maturation, scant information regarding the variability of T cell maturation in children with renal disease is available. In this study, we compared the T cell phenotype in children with renal failure (n=80) with that in healthy children (n=20) using multiparameter flow cytometry to detect markers of T cell maturation, exhaustion, and senescence known to influence immune function. We correlated data with the degree of renal failure (dialysis or nondialysis), prior immunosuppression use, and markers of inflammation (C-reactive protein and inflammatory cytokines) to assess the influence of these factors on T cell phenotype. Children with renal disease had highly variable and often markedly skewed maturation phenotypes, including CD4/CD8 ratio reversal, increased terminal effector differentiation in CD8+ T cells, reduction in the proportion of naïve T cells, evidence of T cell exhaustion and senescence, and variable loss of T cell CD28 expression. These findings were most significant in patients who had experienced major immune insults, particularly prior immunosuppressive drug exposure. In conclusion, children with renal disease have exceptional heterogeneity in the T cell repertoire. Cognizance of this heterogeneity might inform risk stratification with regard to the balance between infectious risk and response to immunosuppressive therapy, such as that required for autoimmune disease and transplantation.


Assuntos
Senescência Celular , Insuficiência Renal Crônica/imunologia , Linfócitos T/fisiologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Fatores de Tempo , Adulto Jovem
11.
Blood ; 125(25): 3835-50, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-25852054

RESUMO

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor ß (TCRß) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Ativação Viral/imunologia , Adolescente , Adulto , Idoso , Criança , Feminino , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
12.
J Surg Res ; 196(2): 241-6, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25801976

RESUMO

BACKGROUND: Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure. MATERIALS AND METHODS: We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells. RESULTS: We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T-cell expansion is required for the increased alloreactivity. CONCLUSIONS: Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR.


Assuntos
Antígenos CD28/metabolismo , Rejeição de Enxerto/metabolismo , Imunologia de Transplantes , Viroses/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Rejeição de Enxerto/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus , Polyomavirus , Viroses/metabolismo
13.
J Immunol ; 189(9): 4387-95, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23002440

RESUMO

Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4(+) and CD8(+) T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c(+) DCs compared with untreated controls. However, DCs isolated from anti-CD154-treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4(+) and CD8(+) T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.


Assuntos
Antígenos CD40/antagonistas & inibidores , Ligante de CD40/antagonistas & inibidores , Citocinas/antagonistas & inibidores , Células Dendríticas/imunologia , Mediadores da Inflamação/antagonistas & inibidores , Animais , Antígenos CD40/fisiologia , Ligante de CD40/fisiologia , Galinhas , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Epitopos de Linfócito T/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Quimera por Radiação , Transdução de Sinais/imunologia
14.
Biol Blood Marrow Transplant ; 19(11): 1638-49, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24047754

RESUMO

We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Linfócitos T/imunologia , Condicionamento Pré-Transplante/métodos , Abatacepte , Doença Aguda , Adolescente , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
15.
Blood ; 118(25): 6580-90, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21989987

RESUMO

In this study, we used the rhesus macaque model to determine the impact that AMD3100 has on lymphocyte mobilization, both alone and in combination with G-CSF. Our results indicate that, unlike G-CSF, AMD3100 substantially mobilizes both B and T lymphocytes into the peripheral blood. This led to significant increases in the peripheral blood content of both effector and regulatory T-cell populations, which translated into greater accumulation of these cells in the resulting leukapheresis products. Notably, CD4(+)/CD25(high)/CD127(low)/FoxP3(+) Tregs were efficiently mobilized with AMD3100-containing regimens, with as much as a 4.0-fold enrichment in the leukapheresis product compared with G-CSF alone. CD8(+) T cells were mobilized to a greater extent than CD4(+) T cells, with accumulation of 3.7 ± 0.4-fold more total CD8+ T cells and 6.2 ± 0.4-fold more CD8(+) effector memory T cells in the leukapheresis product compared with G-CSF alone. Given that effector memory T-cell subpopulations may mediate less GVHD compared with other effector T-cell populations and that Tregs are protective against GVHD, our results indicate that AMD3100 may mobilize a GVHD-protective T-cell repertoire, which would be of benefit in allogeneic hematopoietic stem cell transplantation.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Benzilaminas , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Ciclamos , Sinergismo Farmacológico , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Leucaférese/métodos , Contagem de Linfócitos , Macaca mulatta , Receptores CXCR4/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
16.
J Immunol ; 186(4): 2033-41, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21257960

RESUMO

Donor-reactive memory T cells (Tmem) can play an important role in mediating graft rejection after transplantation. Transplant recipients acquire donor-reactive Tmem not only through prior sensitization with alloantigens but also through previous exposure to environmental pathogens that are cross-reactive with allogeneic peptide-MHC complexes. Current dogma suggests that most, if not all, Tmem responses are independent of the requirement for CD28 and/or CD154/CD40-mediated costimulation to mount a recall response. However, heterogeneity among Tmem is increasingly being appreciated, and one important factor known to impact the function and phenotype of Ag-specific T cell responses is the amount/duration of Ag exposure. Importantly, the impact of Ag exposure on development of costimulation independence is currently unknown. In this study, we interrogated the effect of decreased Ag amount/duration during priming on the ability of donor-reactive Tmem to mediate costimulation blockade-resistant rejection during a recall response after transplantation in a murine model. Recipients possessing donor-reactive Tmem responses that were generated under conditions of reduced Ag exposure exhibited similar frequencies of Ag-specific T cells at day 30 postinfection, but, strikingly, failed to mediate costimulation blockade-resistant rejection after challenge with an OVA-expressing skin graft. Thus, these data demonstrate the amount/duration of Ag exposure is a critical factor in determining Tmem's relative requirement for costimulation during the recall response after transplantation.


Assuntos
Ampicilina/farmacologia , Antígenos/imunologia , Reação Enxerto-Hospedeiro/imunologia , Memória Imunológica , Listeriose/imunologia , Ativação Linfocitária/imunologia , Ovalbumina/imunologia , Subpopulações de Linfócitos T/transplante , Ampicilina/administração & dosagem , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Antígenos/administração & dosagem , Carga Bacteriana/imunologia , Relação Dose-Resposta Imunológica , Reação Enxerto-Hospedeiro/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Listeriose/microbiologia , Listeriose/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Transplante de Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/microbiologia , Fatores de Tempo
17.
J Trauma Acute Care Surg ; 95(1): 39-46, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37038251

RESUMO

BACKGROUND: Thoracic injury can cause impairment of lung function leading to respiratory complications such as pneumonia (PNA). There is increasing evidence that central memory T cells of the adaptive immune system play a key role in pulmonary immunity. We sought to explore whether assessment of cell phenotypes using flow cytometry (FCM) could be used to identify pulmonary infection after thoracic trauma. METHODS: We prospectively studied trauma patients with thoracic injuries who survived >48 hours at a Level 1 trauma center from 2014 to 2020. Clinical and FCM data from serum samples collected within 24 hours of admission were considered as potential variables. Random forest and logistic regression models were developed to estimate the risk of hospital-acquired and ventilator-associated PNA. Variables were selected using backwards elimination, and models were internally validated with leave-one-out. RESULTS: Seventy patients with thoracic injuries were included (median age, 35 years [interquartile range (IQR), 25.25-51 years]; 62.9% [44 of 70] male, 61.4% [42 of 70] blunt trauma). The most common injuries included rib fractures (52 of 70 [74.3%]) and pulmonary contusions (26 of 70 [37%]). The incidence of PNA was 14 of 70 (20%). Median Injury Severity Score was similar for patients with and without PNA (30.5 [IQR, 22.6-39.3] vs. 26.5 [IQR, 21.6-33.3]). The final random forest model selected three variables (Acute Physiology and Chronic Health Evaluation score, highest pulse rate in first 24 hours, and frequency of CD4 + central memory cells) that identified PNA with an area under the curve of 0.93, sensitivity of 0.91, and specificity of 0.88. A logistic regression with the same features had an area under the curve of 0.86, sensitivity of 0.76, and specificity of 0.85. CONCLUSION: Clinical and FCM data have diagnostic utility in the early identification of patients at risk of nosocomial PNA following thoracic injury. Signs of physiologic stress and lower frequency of central memory cells appear to be associated with higher rates of PNA after thoracic trauma. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level IV.


Assuntos
Lesão Pulmonar , Pneumonia , Traumatismos Torácicos , Ferimentos não Penetrantes , Masculino , Humanos , Citometria de Fluxo , Algoritmo Florestas Aleatórias , Traumatismos Torácicos/complicações , Traumatismos Torácicos/diagnóstico , Traumatismos Torácicos/epidemiologia , Lesão Pulmonar/complicações , Ferimentos não Penetrantes/complicações , Pneumonia/complicações , Escala de Gravidade do Ferimento , Estudos Retrospectivos
18.
Blood ; 116(24): 5403-18, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-20833977

RESUMO

We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8(+) and CD4(+) granzyme B(+) effector cells and FoxP3(pos)/CD27(high)/CD25(pos)/CD127(low) CD4(+) T cells. CD8(+) cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-γ, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-resistant CD28(-) CD8(+) T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control.


Assuntos
Antígenos CD28 , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Terapia de Imunossupressão/métodos , Sirolimo/uso terapêutico , Animais , Proliferação de Células , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Haplótipos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ativação Linfocitária , Macaca mulatta , Sirolimo/imunologia
19.
Surgery ; 172(6): 1851-1859, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36116976

RESUMO

BACKGROUND: An emerging body of literature supports the role of individualized prognostic tools to guide the management of patients after trauma. The aim of this study was to develop advanced modeling tools from multidimensional data sources, including immunological analytes and clinical and administrative data, to predict outcomes in trauma patients. METHODS: This was a prospective study of trauma patients at Level 1 centers from 2015 to 2019. Clinical, flow cytometry, and serum cytokine data were collected within 48 hours of admission. Sparse logistic regression models were developed, jointly selecting predictors and estimating the risk of ventilator-associated pneumonia, acute kidney injury, complicated disposition (death, rehabilitation, or nursing facility), and return to the operating room. Model parameters (regularization controlling model sparsity) and performance estimation were obtained via nested leave-one-out cross-validation. RESULTS: A total of 179 patients were included. The incidences of ventilator-associated pneumonia, acute kidney injury, complicated disposition, and return to the operating room were 17.7%, 28.8%, 22.5%, and 12.3%, respectively. Regarding extensive resource use, 30.7% of patients had prolonged intensive care unit stay, 73.2% had prolonged length of stay, and 23.5% had need for prolonged ventilatory support. The models were developed and cross-validated for ventilator-associated pneumonia, acute kidney injury, complicated dispositions, and return to the operating room, yielding predictive areas under the curve from 0.70 to 0.91. Each model derived its optimal predictive value by combining clinical, administrative, and immunological analyte data. CONCLUSION: Clinical, immunological, and administrative data can be combined to predict post-traumatic outcomes and resource use. Multidimensional machine learning modeling can identify trauma patients with complicated clinical trajectories and high resource needs.


Assuntos
Injúria Renal Aguda , Pneumonia Associada à Ventilação Mecânica , Humanos , Estudos Prospectivos , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/etiologia , Aprendizado de Máquina , Modelos Logísticos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Estudos Retrospectivos
20.
J Trauma Acute Care Surg ; 91(1): 47-53, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33660689

RESUMO

BACKGROUND: Flow cytometry (FCM) is a rapid diagnostic tool for monitoring immune cell function. We sought to determine if assessment of cell phenotypes using standardized FCM could be used to identify nosocomial infection after trauma. METHODS: Prospective study of trauma patients at a Level I center from 2014 to 2018. Clinical and FCM data were collected within 24 hours of admission. Random forest (RF) models were developed to estimate the risk of severe sepsis (SS), organ space infection (OSI), and ventilator-associated pneumonia (VAP). Variables were selected using backward elimination and models were validated with leave-one-out. RESULTS: One hundred and thirty-eight patients were included (median age, 30 years [23-44 years]; median Injury Severity Score, 20 (14-29); 76% (105/138) Black; 60% (83/138) gunshots). The incidence of SS was 8.7% (12/138), OSI 16.7% (23/138), and VAP 18% (25/138). The final RF SS model resulted in five variables (RBCs transfused in first 24 hours; absolute counts of CD56- CD16+ lymphocytes, CD4+ T cells, and CD56 bright natural killer [NK] cells; percentage of CD16+ CD56+ NK cells) that identified SS with an AUC of 0.89, sensitivity of 0.98, and specificity of 0.78. The final RF OSI model resulted in four variables (RBC in first 24 hours, shock index, absolute CD16+ CD56+ NK cell counts, percentage of CD56 bright NK cells) that identified OSI with an AUC of 0.76, sensitivity of 0.68, and specificity of 0.82. The RF VAP model resulted in six variables (Sequential [Sepsis-related] Organ Failure Assessment score: Injury Severity Score; CD4- CD8- T cell counts; percentages of CD16- CD56- NK cells, CD16- CD56+ NK cells, and CD19+ B lymphocytes) that identified VAP with AUC of 0.86, sensitivity of 0.86, and specificity of 0.83. CONCLUSIONS: Combined clinical and FCM data can assist with early identification of posttraumatic infections. The presence of NK cells supports the innate immune response that occurs during acute inflammation. Further research is needed to determine the functional role of these innate cell phenotypes and their value in predictive models immediately after injury. LEVEL OF EVIDENCE: Prognostic, level III.


Assuntos
Infecção Hospitalar/diagnóstico , Células Matadoras Naturais/imunologia , Modelos Biológicos , Ferimentos e Lesões/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecção Hospitalar/sangue , Infecção Hospitalar/imunologia , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Humanos , Imunidade Inata , Escala de Gravidade do Ferimento , Tempo de Internação/estatística & dados numéricos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Ferimentos e Lesões/sangue , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/imunologia , Adulto Jovem
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