RESUMO
Allogeneic hematopoietic cell transplantation (alloHCT) provides a potential curative treatment for haematological malignancies. The therapeutic Graft-versus-Leukaemia (GvL) effect is induced by donor T cells attacking patient hematopoietic (malignant) cells. However, if healthy non-hematopoietic tissues are targeted, Graft-versus-Disease (GvHD) may develop. After HLA-matched alloHCT, GvL and GvHD are induced by donor T cells recognizing polymorphic peptides presented by HLA on patient cells, so-called minor histocompatibility antigens (MiHAs). The balance between GvL and GvHD depends on the tissue distribution of MiHAs and T-cell frequencies targeting these MiHAs. T cells against broadly expressed MiHAs induce GvL and GvHD, whereas those targeting MiHAs with hematopoietic-restricted expression induce GvL without GvHD. Recently, the MiHA repertoire identified in natural immune responses after alloHCT was expanded to 159 total HLA-I-restricted MiHAs, including 14 hematopoietic-restricted MiHAs. This review explores their potential relevance to predict, monitor, and manipulate GvL and GvHD for improving clinical outcome after HLA-matched alloHCT.
Assuntos
Doença Enxerto-Hospedeiro , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/genética , Efeito Enxerto vs Leucemia/imunologia , Transplante Homólogo , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Linfócitos T/imunologia , AloenxertosRESUMO
Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.
Assuntos
Antígenos HLA-E , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais , Humanos , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/genética , Aloenxertos , Linfócitos T/imunologia , Polimorfismo Genético , Transplante HomólogoRESUMO
BACKGROUND: Haploidentical hematopoietic stem cell transplant (HSCT) is a curative treatment especially for countries where bone marrow registries are nonexistent. We present our experience with haploidentical HSCT in pediatric patients. METHODS: Retrospective data collected and analyzed for patients ≤18 years, from January 2017 to December 2022. RESULTS: The cohort consisted of 20 patients with median age at transplant of 61.5 (IQR: 124) months. Fourteen (70%) were malignant and 6 (30%) were benign diseases. Donors were father in majority (9/20; 45%). Stem cell source was peripheral blood 8, marrow 8, and combined 4. c-specific antibodies were positive in 6 (30%). Median CD34 cell dose infused: 9.35 × 106/kg. Median engraftment time: 15 (IQR: 17) days. Acute and chronic graft-versus-host disease (GVHD) occurred in 12/20 (60%) and 5/20 (25%), respectively. Complications included infection/sepsis (14/20; 70%), cytomegalovirus reactivation (14/20; 70%), sinusoidal obstruction syndrome (1/20; 5%), primary graft failure (PGF) (6/20; 30%), and secondary graft failure (4/20; 20%). PGF was more common in benign conditions (p = 0.003) and less prevalent in cases with aGVHD (p = 0.007). aGVHD was more common in malignant conditions (p = 0.007). Overall survival (OS), relapse-free survival (RFS), and treatment-related mortality (TRM) were 40%, 50%, and 35%, respectively. Median time of survival and relapse were 8 (IQR: 15) and 9 (IQR: 13) months, respectively. CONCLUSION: OS was comparable to that of other low-middle-income countries. GVHD was a major challenge, along with sepsis and CMV infection. Half of the leukemias relapsed. Graft failure was a major concern in nonmalignant diseases.
Assuntos
Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Transplante Haploidêntico , Humanos , Estudos Retrospectivos , Masculino , Feminino , Criança , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Lactente , Adolescente , Doença Enxerto-Hospedeiro/etiologia , Países em DesenvolvimentoRESUMO
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using umbilical cord blood is a valuable therapy option for patients with acute leukemia (AL). Acute graft-versus-host disease (aGVHD) remains the most frequently encountered complication. This study investigated risk factors for aGVHD and assessed whether post-transplant serum ferritin (SF) within 2 weeks is a potential biomarker for aGVHD in pediatric patients with AL undergoing umbilical cord blood transplantation (UCBT). MATERIAL AND METHODS We conducted a retrospective cohort study of 71 patients with AL who underwent UCBT at the Children's Hospital of Soochow University between 2017 and 2022. We evaluated several factors related to aGVHD. Univariate and multivariate analyses were performed using the proportional subdistribution hazard regression model of Fine and Gray. Analyses of overall survival (OS) were performed using the Kaplan-Meier method, and differences were compared using log-rank tests. RESULTS Of the 71 patients, 23 (32.4%) experienced grade II-IV aGVHD, of whom 18 (25.4%) developed grade III-IV aGVHD. Patients with grade II-IV and III-IV aGVHD had worse 5-year OS (69.4±10%, p=0.01; and 60.6±11.6, P=0.007, respectively). Conditioning intensity was a risk factor for grade III-IV aGVHD (HR: 0.34, 95% CI: 0.13-0.89, P=0.027). An SF level >1650 ng/mL within 2 weeks post-transplant was associated with an increased risk of severe aGVHD (HR: 3.61, 95% CI: 1.09-11.97, P=0.036). CONCLUSIONS Post-transplant SF within 2 weeks was a potential biomarker for developing severe aGVHD. Higher levels of post-transplant SF are associated with a higher incidence of grade II-IV aGVHD and grade III-IV aGVHD.
Assuntos
Biomarcadores , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Ferritinas , Doença Enxerto-Hospedeiro , Humanos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/diagnóstico , Masculino , Feminino , Ferritinas/sangue , Criança , Estudos Retrospectivos , Pré-Escolar , Biomarcadores/sangue , Adolescente , Lactente , Doença Aguda , Leucemia/sangue , Leucemia/terapia , Fatores de Risco , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/terapiaRESUMO
Purpose: To identify molecular signatures specific for ocular graft-versus-host disease (GVHD) by proteomic analysis of corneas from mice with GVHD. Methods: We identified differentially expressed proteins (DEPs) in corneal samples from GVHD model mice and syngeneic control mice 4 weeks after bone marrow transplantation. Data-independent acquisition analysis was performed on individual samples, and the roles of DEPs in biological pathways related to GVHD were evaluated via bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Three important signaling pathways were upregulated in the cornea in mice with GVHD: (1) the necroptosis pathway, (2) the mitogen-activated protein kinase (MAPK) pathway, and (3) as previously reported, the neutrophil extracellular trap (NET) pathway. In those signaling pathways, we identified new upregulated molecules, including (1) receptor-interacting protein kinase 1 (RIPK1), RIPK3, interferon regulatory factor 9, the interferon-induced double-stranded RNA-activated protein kinase lipoxygenase, and high mobility group box1 (HMGB1) which are damage-associated molecular patterns (DAMPs) in the necroptosis pathway; (2) the sequentially upregulated interleukin 1 (IL-1) receptor-associated kinase (IRAK), an evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT), and p38, which is downstream of the IL-1 receptor and increased CDC42/Rac (Rac2), a Rho family GTPase in the MAPK pathway; and (3) the integrin components CR3 and macrophage-1 antigen (MAC-1), which are DAMPs, and the pyroptosis-related protein gasdermin D (GSDMD) in the NET pathway. Conclusions: These novel molecules may help researchers elucidate the pathogenesis of GVHD and identify new therapeutic targets for corneal changes in patients with ocular GVHD.
Assuntos
Córnea , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro , Camundongos Endogâmicos C57BL , Necroptose , Proteômica , Transdução de Sinais , Regulação para Cima , Animais , Camundongos , Necroptose/fisiologia , Doença Enxerto-Hospedeiro/metabolismo , Córnea/metabolismo , Córnea/patologia , Transdução de Sinais/fisiologia , Feminino , Transplante de Medula ÓsseaRESUMO
Introduction: Humanized mouse models to recapitulate human biological systems still have limitations, such as the onset of lethal graft-versus-host disease (GvHD), a variable success rate, and the low accessibility of total body irradiation (TBI). Recently, mice modified with the CD47-SIRPA axis have been studied to improve humanized mouse models. However, such trials have been rarely applied in NOD mice. In this study, we created a novel mouse strain, NOD-CD47nullRag2nullIL-2rγnull (RTKO) mice, and applied it to generate humanized mice. Methods: Four-week-old female NOD-Rag2nullIL-2rγnull (RID) and RTKO mice pre-conditioned with TBI or busulfan (BSF) injection were used for generating human CD34+ hematopoietic stem cell (HSC) engrafted humanized mice. Clinical signs were observed twice a week, and body weight was measured once a week. Flow cytometry for human leukocyte antigens was performed at intervals of four weeks or two weeks, and mice were sacrificed at 48 weeks after HSC injection. Results: For a long period from 16 to 40 weeks post transplantation, the percentage of hCD45 was mostly maintained above 25% in all groups, and it was sustained the longest and highest in the RTKO BSF group. Reconstruction of human leukocytes, including hCD3, was also most prominent in the RTKO BSF group. Only two mice died before 40 weeks post transplantation in all groups, and there were no life-threatening GvHD lesions except in the dead mice. The occurrence of GvHD has been identified as mainly due to human T cells infiltrating tissues and their related cytokines. Discussion: Humanized mouse models under all conditions applied in this study are considered suitable models for long-term experiments based on the improvement of human leukocytes reconstruction and the stable animal health. Especially, RTKO mice pretreated with BSF are expected to be a valuable platform not only for generating humanized mice but also for various immune research fields.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Camundongos Endogâmicos NOD , Camundongos Knockout , Condicionamento Pré-Transplante , Animais , Bussulfano/farmacologia , Humanos , Camundongos , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Células-Tronco Hematopoéticas/metabolismo , Feminino , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/deficiência , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Modelos Animais de Doenças , Irradiação Corporal TotalRESUMO
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.
Assuntos
Interleucina-2 , Isoantígenos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas , Linfócitos T Reguladores , Fator de Crescimento Transformador beta , Tolerância ao Transplante , Animais , Isoantígenos/imunologia , Tolerância ao Transplante/imunologia , Camundongos , Fator de Crescimento Transformador beta/imunologia , Linfócitos T Reguladores/imunologia , Interleucina-2/imunologia , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , FemininoRESUMO
Despite the continuous improvement in the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), acute graft-versus-host disease (GVHD) remains a major complication and cause of death. In recent years, with the emergence of new drugs for the prevention and treatment of acute GVHD and the update of a series of clinical studies, there have been varying degrees of changes in the routine prevention and treatment regimens for acute GVHD. Based on the main research achievements and the accumulation of clinical experience in this field in recent years, this consensus further updates the "The Consensus on Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Diseases in China-Acute Graft-Versus-Host Disease (2020) .
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , China , Consenso , Transplante Homólogo , Doença Aguda , População do Leste AsiáticoRESUMO
Objective: To analyze the causes and demographic characteristics of pre-engraftment mortality in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and investigate the risk factors and measures for preventing pre-engraftment mortality. Methods: A retrospective case analysis, involving a total of 7 427 patients who underwent allo-HSCT at Peking University People's Hospital between January 2016 and July 2023, was conducted. Results: Among the 7 427 patients who underwent allo-HSCT, 56 cases (0.75% ) experienced pre-engraftment mortality. The median time to death for these 56 patients was +7 (-3 to +38) days after stem cell infusion. The median times to death for patients with acute leukemia (AL), severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS) were +11 (-1 to +38), +3 (-1 to +34), and +16 (-1 to +38) days, respectively (P=0.013). The main causes of pre-engraftment mortality were infection (39.3% ), cardiac toxicity (28.6% ), and intracranial hemorrhage (26.8% ). Infection was the most common cause of pre-engraftment mortality in patients with AL and MDS (55.0% and 60.0% ), whereas cardiac toxicity was predominantly observed in patients with SAA (71.4% ), with no cases in patients with AL and only one case in patients with MDS. Among patients who died from intracranial hemorrhage, 53.3% had severe infections. The median times to death for infection, cardiac toxicity, and intracranial hemorrhage was +11 (-1 to +38), +2.5 (-1 to +17), and +8 (-3 to +37) days, respectively (P<0.001) . Conclusions: Infection is the primary cause of pre-engraftment mortality in allo-HSCT, and severe cardiac toxicity leading to pre-engraftment mortality should be closely monitored in patients with SAA.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Fatores de Risco , Síndromes Mielodisplásicas/terapia , Anemia Aplástica/terapia , Doença Enxerto-Hospedeiro/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Leucemia/terapia , Leucemia/mortalidade , AdultoRESUMO
This study aimed to investigate the effect of iron overload on the transplant outcomes of pediatric patients with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A retrospective analysis was conducted on the clinical data of 74 children with SAA who received allo-HSCT at the Hematology Department of Wuhan Children's Hospital between January 2018 and August 2022. Children with iron overload (serum ferritin >1 000 µg/L) before transplantation had a longer disease course, received more red blood cell transfusions, and had a higher number of CD34(+) cells infused. Moreover, iron overload significantly delayed the reconstitution of regulatory T cells after transplantation, increasing the incidence of hemorrhagic cystitis and grade â ¢-â £ acute graft-versus-host disease after transplantation. However, iron overload did not significantly affect the overall survival and failure-free survival rates of the children.
Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Sobrecarga de Ferro , Transplante Homólogo , Humanos , Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sobrecarga de Ferro/etiologia , Estudos Retrospectivos , Criança , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Masculino , Feminino , Pré-Escolar , Taxa de SobrevidaRESUMO
BACKGROUND: Cutaneous graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Phototherapy has been used to treat cutaneous GVHD, but data on its safety and efficacy are sparse. AIM: Review the current medical literature regarding the efficacy, dosing, and safety of various types of phototherapies for the treatment of cutaneous GVHD. METHODS: A systematic review of PubMed, Embase, Cochrane, and ClinicalTrials databases was performed. Publications were screened according to the PRISMA guidelines. Exclusion criteria comprised case reports and case series reporting less than five patients, review articles, and articles not published in English. RESULTS: A total of 28/1304 (2.5%) studies were included. Fifteen studies (n = 267 patients) focused on psoralen and ultraviolet (UV) A (PUVA), in which 65.5% of patients received concomitantly other systemic treatments. The response rate was 89.9%, with a mean of 33.2 treatments. Adverse events were recorded in 54% but were mainly mild. Eight studies, encompassing 95 patients, focused on narrow-band (NB) UVB. A response was observed in 94%, with a mean number of 26 treatments and 8.6% adverse effects. UVA1 was reported in six studies (n = 132 patients). A response was recorded in 89.3% with a mean of 26.2 treatments. Adverse events were noted in 70.1%, with a discontinuation rate of 10.9%. It should be noted that adverse events were recorded during the follow-up period of the studies, which varied significantly, ranging from no follow-up to 31 months. CONCLUSIONS: Current data regarding the use of phototherapy for the treatment of cutaneous GVHD are based on retrospective studies and case series. The present report advocates the use of one of the three modalities of phototherapy as an effective and safe adjunctive treatment for cutaneous GVHD, especially NB UVB phototherapy.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/terapia , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia PUVA , Dermatopatias/terapia , FototerapiaRESUMO
Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
Assuntos
Ácidos e Sais Biliares , Fezes , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Ácidos e Sais Biliares/metabolismo , Humanos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/microbiologia , Microbioma Gastrointestinal/imunologia , Feminino , Masculino , Fezes/microbiologia , Pessoa de Meia-Idade , Doença Aguda , Adulto , Retroalimentação Fisiológica , Imunidade , Metabolômica , Transplante de Células-Tronco Hematopoéticas , MultiômicaRESUMO
Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003-2021, at median age 4.3 years (range 0.5-19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1-185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1-14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Pré-Escolar , Criança , Masculino , Feminino , Lactente , Adolescente , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/diagnóstico , Adulto Jovem , Síndromes de Imunodeficiência/terapia , Síndromes de Imunodeficiência/diagnóstico , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Doenças da Imunodeficiência Primária/terapia , Doenças da Imunodeficiência Primária/diagnósticoRESUMO
Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCRαß, TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/etiologia , Criança , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Pré-Escolar , Estudos Prospectivos , Incidência , Transplante de Medula Óssea/efeitos adversos , Lactente , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Reconstituição Imune , Doença AgudaRESUMO
AIMS: To study the effects of routine HLA screening and the policy of avoiding donor-dominant one-way HLA match to prevent graft-versus-host disease (GVHD) after living donor liver transplantation (LDLT). PATIENTS AND METHODS: The records of potential living liver donors and recipients who attended our center between 2007 and 2018 were reviewed retrospectively. RESULTS: Of the 149 patients who underwent LDLT and survived longer than 3 months, two developed GVHD despite our strict policy. The first patient presented with grade II GVHD limited to the skin. She was treated successfully by briefly discontinuing immunosuppression and switching to everolimus. In the second case, the policy had been relaxed due to the availability of a single donor for ABO-incompatible transplantation without any intervention to decrease anti-A antibody levels (special case: A2 to O). Nevertheless, the patient presented with grade I GVHD limited to skin and was treated successfully by adding oral methylprednisolone to tacrolimus and mycophenolate mofetil. To the best of our information, this is the second reported case who recovered from GVHD after LDLT from a donor, homozygous at HLA A, B and DR and a recipient, heterozygous for all. Sixteen potential donors (1.2% of all candidates) of 14 recipients were disqualified solely on the basis of the HLA results; five of these patients died due to unavailability of another donor. CONCLUSION: The results support the policy of avoiding HLA combinations that preclude immune recognition of graft lymphocytes as foreign to decrease the risk of GVHD after LDLT.
Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA , Teste de Histocompatibilidade , Transplante de Fígado , Doadores Vivos , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Estudos Retrospectivos , Feminino , Masculino , Criança , Pré-Escolar , Antígenos HLA/imunologia , Antígenos HLA/genética , Lactente , Adolescente , Adulto , Imunossupressores/uso terapêuticoRESUMO
After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD.
Assuntos
Citocinas , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Serviços de Assistência Domiciliar , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/etiologia , Citocinas/sangue , Masculino , Feminino , Adulto , Adolescente , Pessoa de Meia-Idade , Suécia , Resultado do Tratamento , Criança , Idoso , Adulto Jovem , Condicionamento Pré-Transplante/métodosRESUMO
Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce cytolysis of tumor cells, and murine experiments demonstrate that activating iNKT cells in vivo or treating mice with ex vivo expanded iNKT cells can reduce tumor burden. More recently, research has focused on testing anti-tumor efficacy of iNKT cells genetically modified to express a chimeric antigen receptor (CAR) protein (CAR-iNKT) cells to enhance iNKT cell tumor killing. Further, several of these approaches are now being tested in clinical trials, with strong safety signals demonstrated, though efficacy remains to be established following these early phase clinical trials. Here we review the progress in the field relating to role of iNKT cells in GVHD prevention and anti- cancer efficacy. Although the iNKT field is progressing at an exciting rate, there is much to learn regarding iNKT cell subset immunophenotype and functional relationships, optimal ex vivo expansion approaches, ideal treatment protocols, need for cytokine support, and rejection risk of iNKT cells in the allogeneic setting.
Assuntos
Doença Enxerto-Hospedeiro , Células T Matadoras Naturais , Células T Matadoras Naturais/imunologia , Humanos , Animais , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/prevenção & controle , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Neoplasias/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pesquisa Translacional Biomédica , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genéticaRESUMO
Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.
Assuntos
Ciclofosfamida , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Sirolimo , Humanos , Sirolimo/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/efeitos adversos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Modelos BiológicosRESUMO
BACKGROUND: Preventing the progression of chronic oral graft-versus-host disease (cGVHD) is essential for maintaining oral health, improving quality of life, minimizing functional impairment, reducing systemic complications, and addressing treatment challenges. PURPOSE: To evaluate the effectiveness of early intervention with oral mucosal barrier protective agents in preventing the progression of cGVHD and its impact on oral health, quality of life, and treatment response. METHODS: This retrospective cohort study included 75 participants, with 34 in the non-oral mucosal barrier protective agent group and 41 in the oral mucosal barrier protective agent group. Baseline characteristics, oral mucosal health parameters, quality of life assessments, and curative effect data were collected and compared between the two study groups. RESULTS: The group receiving oral mucosal barrier protectants (n = 41) exhibited significantly lower severity of oral mucositis compared to the group without such protectants (n = 34) (2.12 ± 0.48 vs. 2.56 ± 0.63, P = 0.001) and the incidence of complications was significantly lower in the group receiving oral mucosal barrier protectants (P < 0.05). Additionally, the quality of life assessment showed marked improvements in somatization, emotional management, and social reintegration in the oral mucosal barrier protectant group compared to the group without these protectants (P < 0.05). Furthermore, the assessment of treatment efficacy revealed significantly higher rates of both complete and partial responses in the oral mucosal barrier protectant group, along with a notable reduction in disease progression compared to the group without these protectants (P < 0.001). CONCLUSION: Early intervention with oral mucosal barrier protective agents was associated with improved oral health parameters, enhanced quality of life, and a more favorable treatment response in the context of cGVHD.