Host-specific cytotoxic T cells against both permissive and nonpermissive HLA-DPB1 mismatches infiltrate the skin at the onset of aGVHD
UPN . | Donor DPB1 (group) . | Host DPB1 (group) . | Mismatches in the GVH direction . | Algorithm prediction of alloreaction . | Skin-derived T-cell clones . | Specificity . |
---|---|---|---|---|---|---|
UPN25,6 | 601/1001 (4/1) | 401/1001 (4/1) | B2705, DR4, DQ8 DP0401 | Permissive | HER-1, HER-28 | DP0401 |
HER-3, HER-30 HER-27, HER-29 | B2705 DQ8 | |||||
UPN36 | 0401/1901 (4/4) | 1301/1901 (4/4) | A1, B17, DR0402 DQ8, DP1301 | Permissive | P11 | DP1301 |
P1, P3, P6, P7, P10 P14 | DQ8 DR0402 | |||||
UPN15,6 | 0301/19 (2/4) | DP0101/19 (4/4) | A201, DP0101 | HVG 0301 ← | A4, D2 | DP0101 |
TM15 | A201 | |||||
UPN53 | 0401/0401 (4/4) | 1001/0401 (1/4) | DP1001 | GVH → 1001 | BV2S1, BV6S7, BV14S1, BV17S1, BV8S1 | DP1001 |
UPN44 | 0301/0401 (2/4) | 0401/0501 (4/4) | DP0501 | HVG 0301← | BV6S7, BV8S1, BV13S1, BV17S1, BV22S1, BV5S2 | DP0501 |
UPN . | Donor DPB1 (group) . | Host DPB1 (group) . | Mismatches in the GVH direction . | Algorithm prediction of alloreaction . | Skin-derived T-cell clones . | Specificity . |
---|---|---|---|---|---|---|
UPN25,6 | 601/1001 (4/1) | 401/1001 (4/1) | B2705, DR4, DQ8 DP0401 | Permissive | HER-1, HER-28 | DP0401 |
HER-3, HER-30 HER-27, HER-29 | B2705 DQ8 | |||||
UPN36 | 0401/1901 (4/4) | 1301/1901 (4/4) | A1, B17, DR0402 DQ8, DP1301 | Permissive | P11 | DP1301 |
P1, P3, P6, P7, P10 P14 | DQ8 DR0402 | |||||
UPN15,6 | 0301/19 (2/4) | DP0101/19 (4/4) | A201, DP0101 | HVG 0301 ← | A4, D2 | DP0101 |
TM15 | A201 | |||||
UPN53 | 0401/0401 (4/4) | 1001/0401 (1/4) | DP1001 | GVH → 1001 | BV2S1, BV6S7, BV14S1, BV17S1, BV8S1 | DP1001 |
UPN44 | 0301/0401 (2/4) | 0401/0501 (4/4) | DP0501 | HVG 0301← | BV6S7, BV8S1, BV13S1, BV17S1, BV22S1, BV5S2 | DP0501 |
UPN1-5 are from References 3-6. Only case UPN5 fits the algorithm shown in Figure 1; most significantly, for UPN1 and UPN4 the T-cell reaction took place in the opposite direction of that expected by the algorithm. Data in bold indicate HLA_DPB1 mismatches in the GVHD direction.
UPN1: A 9-year-old boy with chronic myelogenous leukemia received a graft of his mother's bone marrow. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI): 12 Gy through 6 irradiation courses. GVHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (at days 1, 3, 6, and 11) and 5 mg/d of BB10, an anti–IL-2R antibody, for 10 days. GVHD was first suspected on day 13 and biopsy for culture performed at day 34. The patient died at day 99.
UPN2: A 7-year-old boy received a graft of his mother's bone marrow for acute myelogenous leukemia in the second complete response. The conditioning regimen consisted of TBI and high doses of cytarabine and melphalan. T-cell depletion was performed as GVHD prophylaxis using monoclonal antibody anti-CD2, anti-CD7, and rabbit complement. In addition, the patient received anti-LFA1 and anti-CD2 mAbs from day −3 to day 12. GVHD was suspected on day 19 and biopsy for culture at day 22. The patient died at day 120.
UPN3: A 10-year-old boy with idiopathic myelodysplasia and severe pancytopenia. After the patient failed to engraft with his mother's bone marrow, he received marrow from his father after the following conditioning regimen: busulfan 8 mg/kg over 2 days and cyclophosphamide 200 mg/kg over 4 days. The marrow was T cell–depleted with anti-CD2, anti-CD7, and rabbit complement. Additional in vivo immunotherapy with anti-LFA1 and anti-CD2 was performed as for UPN2. GVHD was diagnosed and skin biopsies performed at day 31 following the second transplantation. The patient died at day 89.
UPN4: A 48-year-old female with chronic myeloid leukemia received a graft from a donor from the French bone marrow transplant registry. Because of GVHD risk factors (patient age, advanced disease, and unrelated donor) and after informed consent, the patient received selected bone marrow (BM) CD34+ cells with the aim of reducing GVHD risk through T-cell reduction. No other GVHD prophylaxis was used except CD34+ selection. Only 3% CD3+ T cells contaminated the CD34 preparation corresponding to a total number of T cells reinjected of 9.4 × 104/kg. GVHD was suspected and skin biopsy performed on day 10. The patient died at day 39.
UPN5: A 42-year-old male with Richter syndrome in first partial response was grafted with unmanipulated noncryopreserved marrow from a female donor. The conditioning regimen consisted of fractionated 12 Gy TBI with lung shielding at 8 Gy followed by cyclophosphamide 60 mg/kg for 2 consecutives days. GVHD prophylaxis consisted of cyclosporine A at a dose of 3 mg/kg/d, together with methotrexate 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6. GVHD was diagnosed and biopsies performed at day 16. The patient died of aspergillosis at day 75. (See References 3-6 for details.)