T cell repertoire complexity is conserved after LLME treatment of donor lymphocyte infusions.
Slow reconstitution of the T cell repertoire after allogeneic blood or bone marrow stem cell transplantation is a major risk factor for patient mortality. The delivery of immunocompetent T cells as delayed donor lymphocyte infusions (DLIs) is a potential way of counteracting this problem. The development of graft-versus-host disease (GVHD) is a potential complication of this procedure, however. We previously found that in P-->F1 haploidentical murine models, the ex-vivo treatment of donor lymphocytes with L-leucyl-L-leucine methyl ester (LLME) can prevent the onset of GVHD after DLI, likely by inducing cell death in most of the perforin-positive CD8(+) T cells and in a fraction of CD4(+) T cells. Our previous preclinical studies have formed the basis of an ongoing phase I clinical trial in which patients received LLME-treated DLI from their original donor in an attempt to accelerate T cell reconstitution. To understand how this treatment strategy might affect the complexity of the DLI T cell repertoire, we used T cell receptor Vbeta spectratype analysis to evaluate the DLI product pre-LLME and post-LLME treatment. The results indicated that the LLME-treated DLI product exhibited CDR3-size distribution complexities similar to those of its untreated donor sample. In addition, comparisons of the CD4(+) and CD8(+) T cell repertoire from the donor before LLME treatment with that of the recipient post-DLI demonstrated equal complexity for most of the resolvable Vbeta families. Finally, the in vitro proliferative capacity of LLME-treated DLI product in response to allo-stimulation in a one-way mixed lymphocyte reaction was comparable to that of the untreated product.
Friedman
Thea M
TM
The Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
Filicko-O'Hara
Joanne
J
Mookerjee
Bijoyesh
B
Wagner
John L
JL
Grosso
Delores A
DA
Flomenberg
Neal
N
Korngold
Robert
R
D000328:Adult; D004151:Dipeptides / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D017710:Lymphocyte Transfusion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000637:transplantation*; D018183:Transplantation Chimera
D004151:Dipeptides; D007166:Immunosuppressive Agents; C045139:leucyl-leucine-methyl ester