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Biol Blood Marrow Transplant. 2018 Nov;24(11):2216-2223. doi: 10.1016/j.bbmt.2018.07.002. Epub 2018 Jul 10.

Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial.

Author information

1
Dana-Farber Cancer Institute, Department of Hematologic Malignancies, Boston, Massachusetts USA.
2
Dana-Farber Cancer Institute, Department of Biostatistics and Computation Biology, Boston, Massachusetts USA.
3
Massachussetts General Hospital Department of Hematology/Oncology, Boston, Massachussetts, USA.
4
Milton Hershey Medical Center, Department of Hematology/Oncology, Hershey, Pennsylvania, USA.
5
University of Chicago, Comprehensive Cancer Center, Chicago, Illinois, USA. University of Utah, Pediatric Hematology/Oncology.
6
Primary Children's Hospital, Salt Lake City, UT, USA.
7
Stanford Hospitals and Clinics, CA, USA.
8
University of Kansas Medical Center, Department of Hematology/Oncology, Kansas City, Missouri, USA.
9
University of North Carolina, Chapel Hill, Division of Hematology/Oncology, North Carolina, USA.
10
Vanderbilt University Medical Center, Department of Hematology/Oncology, Nashville, TN, USA.
11
Texas Transplant Unit, San Antonio, Texas, USA.
12
Fresenius Biotech, Lexington, MA, USA.
13
BMT and Leukemia Program, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25-127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.

KEYWORDS:

ATLG; Immune reconstitution; Naive regulatory T cells

PMID:
30006305
DOI:
10.1016/j.bbmt.2018.07.002

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