CD52/GPI- T-Cells Are Enriched for Alloreactive Specificity and Predict Acute Graft-Versus-Host-Disease After Stem Cell Transplantation
| Autor: | Francesca A M Kinsella, Wayne Croft, Hayden Pearce, Charlotte F. Inman, Charles F Craddock, Jianmin Zuo, Ram Malladi, Sara Barbieri, Paul Moss |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Myeloid
Transplantation Conditioning CD52 T cell medicine.medical_treatment Graft vs Host Disease Antigen medicine Immunology and Allergy Humans IL-2 receptor Alemtuzumab Transplantation business.industry Hematopoietic Stem Cell Transplantation FOXP3 Cell Biology Hematology Immunotherapy medicine.anatomical_structure CD52 Antigen Immunology Cyclosporine Molecular Medicine business medicine.drug |
| Zdroj: | Transplantation and cellular therapy. 27(6) |
| ISSN: | 2666-6367 |
| Popis: | Alemtuzumab is a CD52-specific lympho-depleting antibody. CD52− T cells emerge under alemtuzumab selection pressure. We sought to investigate the phenotype and function of the CD52− T cell fraction and related their presence to clinical outcome. We obtained longitudinal peripheral blood samples from 67 consecutive patients undergoing allo-HSCT between 2013-2016. Forty-seven patients (70%) had a myeloid disease (acute myelogenous leukemia or myelodysplastic syndrome) whereas 20 patients had lymphoid disease. All patients received in vivo alemtuzumab (10 mg/d from day −5 for 5 days) as part of their conditioning protocol. Sixty-three (94%) received reduced-intensity conditioning chemotherapy, whereas 4 (6%) received a myeloablative regimen. All patients received post-transplantation cyclosporine A for graft-versus-host disease (GVHD) prophylaxis. Six (9%) also received methotrexate, whereas 2 (3%) patients also received mycophenolate mofetil. Overall survival at 2 years was 68%, and relapse-free survival was 48%. Twenty-none percent of patients experienced acute GVHD (grade 2 or above), and 15% developed chronic GVHD. CD52− T cells were detectable in 66 of 67 consecutive patients. CD52− T cells demonstrated low binding of fluorescent aerolysin, indicating downregulation of the glycophosphatidylinositol anchor, although we did not detect any mutations in the PIG-A gene as is typically seen in patients with paroxysmal nocturnal hemoglobinuria. CD52− T cells were almost exclusively CD4+ and exhibited a dominant memory phenotype with only small numbers of CD25+ CD127low Foxp3+ regulatory T cells. CD52− T cells exhibited alloreactive specificity in vitro and have a distinct TCR repertoire to CD52+ T cells. Early after allo-hematopoietic stem cell transplantation, the presence of a significant population of CD52− T cells (comprising >51% of the T cell fraction) was found to be an independent risk factor for acute GvHD. This was confirmed in a validation cohort of 28 patients obtained between 2017-2018. These data suggest that the CD52− T cell fraction may represent a residual "footprint" of an early CD4+ T cell alloreactive response and may have been rescued from alemtuzumab-mediated lysis by antigen engagement in vivo. These data help to delineate the nature of T cell escape from alemtuzumab surveillance and contribute to increasing interest in the importance of CD4+ T cells in alloreactive immune responses, which could help inform immunotherapy protocols. |
| Databáze: | OpenAIRE |
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