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Bone Marrow Transplantation Apr 2022The majority of contemporary allogeneic hematopoietic stem cell transplantation (HCT) procedures utilize partially HLA-mismatched stem cell grafts. Donor-specific... (Review)
Review
The majority of contemporary allogeneic hematopoietic stem cell transplantation (HCT) procedures utilize partially HLA-mismatched stem cell grafts. Donor-specific anti-HLA antibodies (DSA) are associated with primary graft failure independent of the graft source, conditioning intensity and other patient and donor factors. Here we provide an update on testing and monitoring of DSA, review the impact of DSA on stem cell engraftment, and present promising desensitization modalities. Ultimately, we attempt to provide practical recommendations for DSA screening and mitigation strategies.
Topics: Antibodies; Antilymphocyte Serum; HLA Antigens; Hematopoietic Stem Cell Transplantation; Humans; Stem Cell Transplantation; Tissue Donors
PubMed: 35082370
DOI: 10.1038/s41409-022-01578-w -
Transplantation Reviews (Orlando, Fla.) Dec 2023Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic review aims to reevaluate, based on actual studies, the effects of different antibody preparations when used in specific KTR subgroups.
METHODS
We searched MEDLINE and CENTRAL and selected randomized controlled trials (RCT) and observational studies looking at different antibody preparations used as induction in KTR. Comparisons were categorized into different KTR subgroups: standard, high risk of rejection, high risk of delayed graft function (DGF), living donor, and elderly KTR. Two authors independently assessed the risk of bias.
RESULTS
Thirty-seven RCT and 99 observational studies were finally included. Compared to anti-interleukin-2-receptor antibodies (IL2RA), anti-thymocyte globulin (ATG) reduced the risk of acute rejection at two years in standard KTR (RR 0.74, 95%CI 0.61-0.89) and high risk of rejection KTR (RR 0.55, 95%CI 0.43-0.72), but without decreasing the risk of graft loss. We did not find significant differences comparing ATG vs. alemtuzumab or different ATG dosages in any KTR group.
CONCLUSIONS
Despite many studies carried out on induction treatment in KTR, their heterogeneity and short follow-up preclude definitive conclusions to determine the optimal induction therapy. Compared with IL2RA, ATG reduced rejection in standard-risk, highly sensitized, and living donor graft recipients, but not in high DGF risk or elderly recipients. More studies are needed to demonstrate beneficial effects in other KTR subgroups and overall patient and graft survival.
Topics: Humans; Aged; Antilymphocyte Serum; Immunosuppressive Agents; Kidney Transplantation; Alemtuzumab; Antibodies; Graft Rejection; Lymphocytes; Transplant Recipients; Graft Survival
PubMed: 37774445
DOI: 10.1016/j.trre.2023.100795 -
Annals of Transplantation May 2018Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy... (Review)
Review
Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable.
Topics: ABO Blood-Group System; Animals; Antilymphocyte Serum; Child; Graft Survival; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lymphoproliferative Disorders; Rabbits; Receptors, Interleukin-2; Registries; Retrospective Studies; Steroids; T-Lymphocytes
PubMed: 29760372
DOI: 10.12659/AOT.908243 -
Transfusion Clinique Et Biologique :... Sep 2019The complement is a key player of the innate immune response. It provides defense mechanisms that are not specific, but very efficient at neutralizing any invader,... (Review)
Review
The complement is a key player of the innate immune response. It provides defense mechanisms that are not specific, but very efficient at neutralizing any invader, accounting for 4% of the proteins in the peripheral blood. Nevertheless, there is a dark side to the complement system, as it may activate its machinery against healthy cells such as peripheral blood red blood cells and platelets resulting in undesired hemolysis and thrombocytopenia, respectively. Understanding and identifying the role of complement in these settings allow physicians to adjust their diagnostic and therapeutic modalities accordingly. The role of complement in the pathophysiology and management of autoimmune hemolytic anemia and of alloimmune-mediated thrombocytopenia is under investigation and discussed.
Topics: Anemia, Hemolytic, Autoimmune; Antibody Specificity; Antigens, Human Platelet; Antilymphocyte Serum; Autoantibodies; Complement System Proteins; Humans; Immunity, Innate; Immunoglobulin G; Immunoglobulin M; Platelet Transfusion
PubMed: 31277985
DOI: 10.1016/j.tracli.2019.06.232 -
Bone Marrow Transplantation Nov 2023Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail...
Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS.
Topics: Aged; Humans; Antilymphocyte Serum; Peripheral Blood Stem Cells; Transplantation, Haploidentical; Neoplasm Recurrence, Local; Cyclophosphamide; Peripheral Blood Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning; Retrospective Studies
PubMed: 37596473
DOI: 10.1038/s41409-023-02085-2 -
Haematologica Oct 2019
Topics: Anemia, Aplastic; Antilymphocyte Serum; Child; Humans; Immunosuppression Therapy; United States
PubMed: 31575670
DOI: 10.3324/haematol.2019.225870 -
Xenotransplantation Jan 2019A long-segmental tracheal lesion is difficult to repair by tracheal allotransplantation due to the lack of a well-defined blood supply for blood vessel anastomosis. The...
BACKGROUND
A long-segmental tracheal lesion is difficult to repair by tracheal allotransplantation due to the lack of a well-defined blood supply for blood vessel anastomosis. The donor trachea needs to be revascularized within a well-vascularized soft tissue flap for several months to allow successful trachea allotransplantation. To date, xenotransplantation using the wild-type or genetically modified pig has been widely studied. The object of this study was to evaluate the feasibility of a small-sized (2 × 2 cm) wild-type pig tracheal patchy in a dog tracheal defect model before trying a long-segment tracheal defect model and using a genetically modified pig as a donor in dog xenotransplantation.
METHOD
Three healthy beagle dogs (8-9 kg) were used as recipients, and one pig (20 kg) was used as the donor. A pig cartilaginous tracheal patchy (2 × 2 cm half tube) was sutured to the tracheal resected site in each dog. Antithymocyte globulin (2.5 mg/kg infusion, D0 and 1), tacrolimus (4.5 mg/kg, twice a day for 2 months), and methylprednisolone sodium succinate (1 mg/kg, IV, for 2 days and tapering) were administered for immunosuppression. The levels IL-2 and IFN-γ in the serum were measured at D0, 7, and 28. Tracheoscopy was performed at D28, 60, and 90. The recipients were sacrificed at D90, and the expression of dog and pig genes in the graft was evaluated by PCR. Histopathological examination of the graft was conducted.
RESULTS
All of the dogs survived without complications during the experimental period. Their IL-2 and IFN-γ levels were significantly increased at D7 after transplantation compared to D0 and D28 (P < 0.05). The pig tracheal patchy site was open, and no stenosis was observed until D90 on tracheoscopy, when pale mucosa erosion was observed; there was also remnant suture material at D28. However, the tracheal patchy sites gradually became similar to normal mucosa at D60 and 90. The expression of pig genes was detected in the graft by PCR. Normal epithelium and CD3 cells were observed in the histological examination at D90.
CONCLUSION
In this study, our data suggest that the pig tracheal patchy can be successfully engrafted into the trachea of dog, although erosion of mucosa on the graft was seen at D30, in spite of the discordant species.
Topics: Animals; Antilymphocyte Serum; Dogs; Heterografts; Immunosuppressive Agents; Swine; Tacrolimus; Trachea; Transplantation, Heterologous; Transplants
PubMed: 30117191
DOI: 10.1111/xen.12452 -
Transplant International : Official... Mar 2015Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for... (Review)
Review
Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.
Topics: Animals; Antilymphocyte Serum; Graft Rejection; Heart Transplantation; Humans; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Rabbits
PubMed: 25363471
DOI: 10.1111/tri.12480 -
Blood Advances Aug 2022A common method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is...
A common method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate, and antithymocyte globulin (ATG). The use of posttransplant cyclophosphamide (PTCy) showed promise in a prospective trial for MMUD HCT. We compared 1-year graft-versus-host disease-free, relapse-free survival (GRFS) in 128 recipients of prophylaxis based on tacrolimus/methotrexate/ATG (ATG group, n = 46) vs PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, n = 82) after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥1 locus among HLA-A, HLA-B, HLA-C, and HLA-DRB1 were included. The 2 groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% vs 26%; P = .01) and >1 locus HLA-mismatched (30.5% vs 2.2%; P = .001) grafts. The 1-year GRFS was 16% (95% confidence interval (CI): 8%-31%) vs 54% (95% CI: 44%-66%; P < .001) in the ATG and PTCy groups, respectively. The multivariable adjusted hazard ratio for GRFS was 0.34 (95% CI: 0.21-0.55; P < .001) with the use of PTCy. The 1-year overall survival in the ATG group was 45% (95% CI: 32%-62%) vs 75% (95% CI: 66%-85%) in the PTCy group (P < .001). Relapse incidence was similar. One-year nonrelapse mortality was greater after ATG-based prophylaxis: 38% (95% CI: 23%-52%) vs 16% (95 CI: 9%-25%), P < .001. In summary, PTCy-based prophylaxis resulted in superior GRFS and overall survival in recipients of MMUD.
Topics: Antilymphocyte Serum; Cyclophosphamide; Graft vs Host Disease; Humans; Methotrexate; Prospective Studies; Tacrolimus; Unrelated Donors
PubMed: 35793451
DOI: 10.1182/bloodadvances.2022007596 -
The Lancet. Haematology Mar 2024Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who...
BACKGROUND
Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG.
METHODS
SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 μg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed.
FINDINGS
54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment.
INTERPRETATION
Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated.
FUNDING
Novartis Pharmaceuticals.
Topics: Adult; Female; Humans; Male; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Hydrazines; Pyrazoles; Drug Therapy, Combination
PubMed: 38335978
DOI: 10.1016/S2352-3026(23)00395-2