Effect of T cell subset dose on outcome of T cell-depleted bone marrow transplantation

Abstract

Summary:T cell depletion of allogeneic stem cell grafts is a highly T cell depletion using the murine monoclonal antibody effective means of reducing the severity and incidence of (moAb) T 10 B 9 is unique in that the T cell receptor acute GVHD. 1 The beneficial effects of T cell depletion are (TCR)␥␦ bearing subset is relatively spared compared counterbalanced by increased graft rejection and, for some to the TCR␣␤ ؉ subset. We evaluated the probabilities diseases, a marked increase in the rate of leukemia of engraftment, acute and chronic graft-versus-host disrelapse. 2,3 It has been hypothesized that acute GVHD may ease (GVHD), relapse, and survival in 273 recipients of be decreased without an increase in leukemia relapse by marrow T cell depleted using T 10 B 9 . Sixty-two patients received marrow from an HLA-identical sibling, 54depletion of selected subsets of T cells from the donor patients received partially matched related donor margraft. 4 In contrast, high rates of graft rejection appear to be row and 157 patients received unrelated donor marrow.most strongly associated with methods resulting in rigorous Limiting dilution analysis (LDA) was used to estimate depletion of all lymphoid cells. 5 Engraftment of T celltotal clonable T cell dose in all patients and a modified depleted (TCD) marrow is also influenced by the intensity LDA using moAb-coated immunomagnetic beads was of the pretransplant conditioning regimen and by immunoused to estimate TCR␣␤ ؉ , CD4 + and CD8 ؉ T cells in suppressive treatment during the early post-transplant a subset of patients. TCR␥␦ ؉ cell dose was estimated period. 6 Both engraftment and acute GVHD rates are by flow cytometry. Cox proportional hazards regression influenced by donor/recipient relationship and histocompatmodels were used to assess the impact of T cell subset ibility. 3 The dose and/or subset of T cells needed to reduce dose/kg of body weight on outcome. We found a signifithe likelihood of rejection vs those which result in an unaccant association of TCR␥␦ ؉ T cell dose (P = 0.004), but ceptable incidence of acute GVHD is difficult to define. In not TCR␣␤ ؉ T cell dose or total clonable T cell dose, the absence of post-transplant chemoprophylaxis, as few as with the probability of engraftment. TCR␣␤ ؉ , CD4 ؉ , 10 5 clonable T cells/kg appear sufficient to induce acute CD8 ؉ and total clonable T cell dose were significantly GVHD after an HLA-identical sibling transplant. 7 The dose associated (P Ͻ 0.001) with the risks of grade 2-4 acute associated with acute GVHD is less well defined for recipi-GVHD in recipients of marrow from related donors but ents of HLA disparate or unrelated transplants. 8,9 not in recipients of marrow from unrelated donors.T 10 B 9 -1A3 (T 10 B 9 ) is an IgM moAb developed at the Neither total clonable T cell dose nor any T cell subset University of Kentucky, and has been used clinically for T dose was found to be significantly associated with cell depletion of donor marrow for more than 10 years. chronic GVHD, relapse or survival. ...

Long term disease-free survival in acute leukemia patients recovering with increased γδ T cells after partially mismatched related donor bone marrow transplantation

“…Several post BMT studies have shown transient increases in gd T cells [44][45][46] but have not associated this finding with GvHD, although Tsuji 47 found that gd T cells could be recruited to lesions and activated by CD4 þ ab T cells. Kawanishi 36 studied 273 recipients of T10B9 T cell-depleted bone marrow graft (62 from HLA-matched sibling donors, 54 PMRD and 157 unrelated donors) and showed that the gd T cell dose was not associated with the risk of acute or chronic GvHD.…”

“…29 These patients were four times more likely to survive disease-free compared to patients who recovered with normal or lower numbers of this specific T cell subset. As activated gd T cells were shown to facilitate alloengraftment, 35,36 we censored all patients before day þ 59 (the earliest gd T cell population recovery), thereby excluding patients who succumb to early transplant mortality or non-engraftment, and decreasing the likelihood of a selective bias. Given the small number of patients who recovered with increased gd T cells, there were limitations to a more extensive and conclusive analysis.…”

High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation

“…Medical records were reviewed to identify all patients at least 18 years old who underwent an initial alloSCT at MSKCC between January 1993 and December 2001. T-cell depletion was performed on bone marrow or peripheral blood stem cells by either soybean agglutination followed by rosetting with sheep red blood cells, 22 T 10 B 9 -1A3, 23 or Isolex 300i (Nexell Therapeutics, Irvine, CA, USA) followed by rosetting with sheep red blood cells.…”

Clinical-scale single-step CD4+ and CD8+ cell depletion for donor innate lymphocyte infusion (DILI)

“…Several in vitro and in vivo studies have shown that gd T cells and NK cells induce potent antitumor effects without causing GVHD. [28][29][30][31] In addition, these innate lymphocytes may facilitate engraftment of human stem cells [32][33][34] and are even able to prevent or mitigate GVHD. 35 These findings are consistent with a recent analysis by Godder et al, 36 who demonstrated a long-term survival advantage without increased GVHD incidence in a group of high-risk acute leukemia patients recovering with increased gd T cells after partially mismatched related donor marrow transplantation.…”