Early CDS T-cell recovery and sensitized cytotoxic T cell response correlate with marrow graft rejection following bone marrow transplantation (BMT) with a nonmyeloablative regimen Article

cited authors

  • Kraus, A; Spitzer, T; Lee, S; Toh, HC; Shaffer, J; McAfee, S; Sackstein, R; Colby, C; Preffer, F; Saidmar, S; Dombkowski, D; Weymouth, D; Sykes, M

fiu authors

abstract

  • A novel nonmyeloablative conditioning regimen for allogeneic BMT has shown efficacy in patients with chemotherapy-refractory hématologie malignancies. The majority cf patients who receive this regimen have achieved lasting allogeneic chimerism. We present data here on patients who demonstrated initial mixed chimerism, then lost their donor marrow graft. The patients received Cyclophosphamide 50mg/kg/day on days -6 to-3 (n=2) or -5 to -3 (n=15), Antithymocyte Globulin (ATG) 15mg/kg (n=10) or 20mg/kg/day (n=7) days -1,1,3 and 5, thymic irradiation (7 Gy) day -1 (n=7) and HLA-identical siblin ; BMT. Donor leukocyte infusion (DLI) was given to patients without GvHD or suspecte 1 GvHD. Increased early circulating CDS T-cell counts between days 35-100 were observe 1 in 7 rejecting patients compared to 10 concurrent non-rejecting patients (table, p<0.05\ The CD4 T-cells, measured at the same time points, did not show a significant differenc : (table, p0.05). The development of sensitized anti-donor CTL responses was associate 1 with rejection in five of five patients. Rejector Patient #1 engrafted on day 14 and develope initial mixed chimerism, which declined after day 20 to become undetectable by day 43. Because of suspected GvHD on day 35, she did not receive DLL CDS T cell concentrations were approximately 200/ul from the time of engraftment until day 80, then increased to a peak of 1000/uI on day 140. On day 100 and 6 months post-BMT, an anti-donor CML response was present in bulk culture and was stronger than that against third party HLA-mismatched cells. A high frequency of anti-donor CTL precursors (CTLp) was measurable in limiting dilution assay (LDA) performed on day 60 (1 in 6899 PBMC). Rejector Patient #2 engrafted on day 29 and also developed initial chimerism, which declined after day 35 and became undetectable after the first DL1 on day 42. A second DLI given on day 61 did not reverse the loss of chimerism. CDS T-cell counts increased rapidly after engraftment to 400/ul. By day 60, a strong anti-donor CTL response and high anti-donor CTLpf were measured (1 in 5457). CTLp were also measurable on day 14 (1 in 57910 PBMC). This patient had high CD4 T-cell counts (1107/ul), which declined by 60 days after BMT (275/ul). A high antidonor IL-2-producing helper cell frequency was measured on day 14 (1 in 18239), and became unmeasurable by day 60. In three other rejectors the anti-donor CML response was positive in bulk culture. CDS T-cells in those patients rose to peak levels of 1616/ul, 1692/ nl and 346/ul respectively between days 50-100. A control non-rejector patient showed low CDS T cell counts (e.g. 13/ul CDS T cells on day 60) and no anti-donor CML response in bulk culture on day 60. In rejectors of donor marrow, loss of donor chimerism correlates with elevated early CDS T-cell counts and anti-donor CTL responses. In one patient we observed high anti-donor IL-2-producing cell frequencies in correlation with elevated CD4 T-cells, suggesting a possible role for CD4 Th in addition to CTL in rejection of donor marrow. Median subset T-cell counts/ul: rejector CDS/CD4 non-rejector CDS/CD4 Day 35-40 168 89 41 70 Day 50-60 374 56 93- 93 Day 75-100 346 101 144 80.

publication date

  • December 1, 2000

volume

  • 96

issue

  • 11 PART I