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Frontiers in Immunology 2023Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to...
Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to immunosuppressive therapy (IST) consisting of a course of anti-thymocyte globulin (ATG) followed by long-term use of ciclosporin. However, the immune response that underlies the pathogenesis of AA remains poorly understood. In this study, we applied high-dimensional mass cytometry on bone marrow aspirates of AA patients pre-ATG, AA patients post-ATG and healthy donors to decipher which immune cells may be implicated in the pathogenesis of AA. We show that the bone marrow of AA patients features an immune cell composition distinct from healthy donors, with significant differences in the myeloid, B-cell, CD4 and CD8 T-cells lineages. Specifically, we discovered that AA pre-ATG is characterized by a disease-specific immune cell network with high frequencies of CD16 myeloid cells, CCR6 B-cells, Th17-like CCR6 memory CD4 T-cells, CD45RACCR7CD38 CD8 T-cells and KLRG1 terminally differentiated effector memory (EMRA) CD8 T-cells, compatible with a state of chronic inflammation. Successful treatment with IST strongly reduced the levels of CD16 myeloid cells and showed a trend toward normalization of the frequencies of CCR6 B-cells, CCR6 memory CD4 T-cells and KLRG1EMRA CD8 T-cells. Altogether, our study provides a unique overview of the immune landscape in bone marrow in AA at a single-cell level and proposes CCR6 as a potential new therapeutic target in AA.
Topics: Humans; Anemia, Aplastic; Bone Marrow; CD8-Positive T-Lymphocytes; Cyclosporine; Pancytopenia; Antilymphocyte Serum
PubMed: 38094307
DOI: 10.3389/fimmu.2023.1274116 -
American Journal of Transplantation :... Sep 2018
Topics: Antilymphocyte Serum; Child; Heart Transplantation; Humans; Incidence; Tissue Donors
PubMed: 29947127
DOI: 10.1111/ajt.14986 -
Journal of Clinical Oncology : Official... Dec 2017
Topics: Antilymphocyte Serum; Double-Blind Method; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Prospective Studies; T-Lymphocytes
PubMed: 29087771
DOI: 10.1200/JCO.2017.76.0512 -
Transplantation and Cellular Therapy Mar 2024Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale...
Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale worldwide. Our patient outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional graft-versus-host disease (GVHD) prophylaxis measure. This was a retrospective analysis of 60 haplo-HSCT recipients using a myeloablative conditioning regimen with antithymocyte globulin and PTCy for GVHD prophylaxis. At 5 years, overall survival was 59.2%, relapse-free survival (RFS) was 48.6%, and chronic GVHD (cGVHD) and relapse-free survival was 40%. The median time to neutrophil and platelet engraftment was 16 days and 28.5 days, respectively. The rates of grade II-IV acute GVHD and extensive cGVHD were 46.7% and 23.3%, respectively. The cumulative incidence of relapse was 30%, nonrelapse mortality was 21.6%, and transplantation-related mortality was 11%. Higher Disease Risk Index and 50% HLA match were associated with lower RFS. Female donor to male recipient and older donor age were associated with an elevated risk of cGVHD. The use of PTCy might not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials, including optimal graft source and donor, date of calcineurin inhibitor initiation, personalized or targeted dose of PTCy, immune reconstitution, and others.
Topics: Female; Humans; Male; Antilymphocyte Serum; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Neoplasm Recurrence, Local; Retrospective Studies; Transplantation Conditioning
PubMed: 38185379
DOI: 10.1016/j.jtct.2024.01.054 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2022To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship...
OBJECTIVE
To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship between the expression of granulocyte colony stimulating factor (G-CSF) and immune dysfunction.
METHODS
A total of 34 children with AA treated in our hospital from December 2016 to September 2018 were selected. All the children received immunosuppressive therapy (IST) for 6 months. According to whether the children had immune dysfunction after 6 months of treatment, they were divided into occurrence group and non occurrence group. General information and laboratory indices were compared between the two groups, and serum G-CSF level was tested, the relationship between serum G-CSF level and immune dysfunction in AA children after treatment with IST was observed and analyzed.
RESULTS
After treatment with IST for 6 months, 12 cases developed immune dysfunction (35.29%). Serum interferon (IFN)-γ level of the occurrence group was higher but G-CSF level was lower than those of the non occurrence group (P<0.05), while the difference of other baseline data was not statistically significant (P>0.05). Multiple regression analysis showed that overexpression of serum IFN-γ and low expression of G-CSF were both the influencing factors of immune dysfunction in AA children after IST treatment (OR>1, P<0.05). ROC curve was drawn, and the result showed that the area under the curve (AUC) of serum G-CSF level predicted the risk of immune dysfunction after IST was 0.843>0.80, when the index cut-off value was set at 6.614 pg/ml, the predictive value was ideal.
CONCLUSION
AA children have a higher risk of immune dysfunction after IST, which may be related to the low expression of serum G-CSF. The detection of serum G-CSF expression can be considered to predict the risk of immune dysfunction in AA children after IST, so as to guide early clinical intervention.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Child; Cyclosporine; Granulocyte Colony-Stimulating Factor; Humans; Immunity; Immunosuppressive Agents
PubMed: 35680811
DOI: 10.19746/j.cnki.issn.1009-2137.2022.03.025 -
Cells Oct 2021Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T... (Review)
Review
Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.
Topics: Adult; Antilymphocyte Serum; Bone Marrow; Bone Marrow Failure Disorders; Humans; Prospective Studies
PubMed: 34831130
DOI: 10.3390/cells10112905 -
Nefrologia : Publicacion Oficial de La... 2016Steroid minimization after kidney transplantation has become more widely practiced as transplant clinicians seek the potential benefits such as reduced cardiovascular... (Review)
Review
Steroid minimization after kidney transplantation has become more widely practiced as transplant clinicians seek the potential benefits such as reduced cardiovascular risk factors, improved growth in pediatric patients, and improved compliance with the immunosuppression regimen. Steroid avoidance (i.e. no steroids after the first week) is generally favored compared to later withdrawal. Induction therapy is routine in this setting, frequently rabbit antithymocyte globulin (rATG, Thymoglobulin®) or off-license use of alemtuzumab. Direct comparisons of steroid minimization regimens versus standard steroid regimens are rare. However, the available data show that the risk of acute rejection is low when rATG or alemtuzumab induction is given to support steroid-avoidance regimens after kidney transplantation. Steroid avoidance may be inadvisable in patients at high immunological risk or at risk of recurrent glomerular disease. Steroid withdrawal after day 8 may be possible without additional risk of rejection in patients given rATG induction, but while encouraging, the data are too sparse for firm conclusions. In summary, steroid avoidance may be beneficial for patients after renal transplantation, with the potential to avoid or reduce steroid-related comorbidities. Whilst depleting induction therapy could be the treatment of choice, results of prospective randomized, controlled studies are eagerly awaited.
Topics: Alemtuzumab; Animals; Antilymphocyte Serum; Cardiovascular Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Depletion; Risk Factors; Steroids
PubMed: 27184648
DOI: 10.1016/j.nefro.2016.03.019 -
Clinical Transplantation Oct 2021Approximately 50% of heart transplant (HT) programs utilize induction therapy (IT) with interleukin-2 receptor antagonists (IL2RA) or polyclonal anti-thymocyte...
BACKGROUND
Approximately 50% of heart transplant (HT) programs utilize induction therapy (IT) with interleukin-2 receptor antagonists (IL2RA) or polyclonal anti-thymocyte antibodies (ATG).
METHODS
Adult HT recipients were identified in the UNOS Registry between 2010 and 2020. We compared mortality between IT strategies with competing risk analysis.
RESULTS
A total of 28 634 HT recipients were included in the study (50.1% no IT, 21.3% ATG, 27.9% IL2RA, .7% alemtuzumab, .01% OKT3). Adjusted all-cause, 30 day and 1 year mortality were lower among those treated with IT than no IT (sub-hazard ratio [SHR] .87, 95% CI .79-.96, SHR .86, .76-.97, SHR .76, .63-.93, P = .007, respectively). In propensity score matching analysis IT was associated with lower 30-day and 1-year mortality. IL2RA had higher all-cause and 1-year mortality than ATG (SHR 1.41, 95% CI 1.23-1.69 and 1.55, 95% CI 1.29-1.88, respectively). Utilization of IT was associated with significantly lower risk of treated rejection at 1 year after HT compared with no IT (relative risk ratio [RRR] .79) and similarly ATG compared with IL2RA (RRR .51).
CONCLUSION
IT was associated with lower mortality and treated rejection episodes than no IT. IL2RA is the most used IT approach but ATG has lower risk of treated rejection and mortality.
Topics: Adult; Antilymphocyte Serum; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation
PubMed: 34296798
DOI: 10.1111/ctr.14440 -
Expert Opinion on Investigational Drugs Aug 2016Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders.... (Review)
Review
INTRODUCTION
Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor's immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40-60% of alloHSCT recipients.
AREAS COVERED
In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention.
EXPERT OPINION
A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.
Topics: Animals; Antilymphocyte Serum; Calcineurin Inhibitors; Cytokines; Drug Design; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Neoplasms
PubMed: 27110922
DOI: 10.1080/13543784.2016.1182498 -
Experimental and Clinical... Aug 2022Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We evaluated the impact of antithymocyte globulin on graft function and related parameters during isothermic blood cardioplegia.
MATERIALS AND METHODS
In this prospective and randomized single center study, 30 patients with orthotropic heart transplant were divided into 2 groups: group 1 included 15 patients who received retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation.
RESULTS
Study patients had a mean age of 33.8 years (range, 15-56 y). All patients had panel reactive antibody less than 10% except for 3 patients. The cluster of differentiation 3-positive cell count decrease was more than 20%. The inotropic therapy dose required and the myocardial pressure (stiffness) were less for group 1 patients. These patients had less acute rejection episodes than group 2 (0% vs 13.3%; P < .05).
CONCLUSIONS
Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the early posttransplant period. Intraoperative antithymocyte globulin treatment may have a preventive effect for acute cellular rejection in heart transplant patients.
Topics: Adult; Antilymphocyte Serum; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Prospective Studies; Tissue Donors; Treatment Outcome
PubMed: 30251943
DOI: 10.6002/ect.2017.0230