Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process.
In this study, we investigated the possibility of selective depletion of donor alloantigen-specific T cells from C57BL/6 (H-2(b)) mice to prevent graft-versus-host disease (GVHD). These cells were first activated with irradiated BALB/c (H-2(d)) host spleen cells in a 5-day mixed lymphocyte culture. Following this activation, a photoactive rhodamine derivative called 4,5-dibromorhodamine 123 (TH9402), was added. This compound is selectively retained in the mitochondria of activated host-reactive cells but not tumor- or third-party-specific resting cells. The treated cells were subsequently exposed to visible light (514 nm) to deplete the TH9402-enriched activated host-reactive cells. Treatment with photodynamic cell purging process (PDP) inhibited antihost responses measured by cytotoxic T lymphocytes (CTL) by 93%, and interferon-gamma production by 66%. By contrast, anti-BCL1 (BALB/c-origin leukemia/lymphoma) and anti-third-party C3H/HeJ (H-2(k)) responses were preserved. PDP-treated primed C57BL/6 cells were further tested in vivo. All lethally irradiated BALB/c mice inoculated with BCL1 cells and T-cell-depleted bone marrow cells developed leukemia by day +30, with 50% mortality by 100 days. All mice died of GVHD after addition of 5 x 10(6) untreated primed C57BL/6 cells. However, addition of same numbers of PDP-treated cells allowed 90% of the recipients to survive more than 100 days without detectable BCL1 tumor cells and free of GVHD. Moreover, PDP-treated primed C57BL/6 cells retained the ability to induce GVHD in the third-party C3H/HeJ mice. These data suggest that PDP can selectively deplete host alloantigen-specific T cells for GVHD prevention and immune and antileukemia function preserve.
Chen
Benny J
BJ
Bone Marrow Transplantation Program, Duke University Medical Center, Durham, NC 27705, USA.
Cui
Xiuyu
X
Liu
Congxiao
C
Chao
Nelson J
NJ
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000528:radiation effects; D006648:Histocompatibility / Q000528:radiation effects; D008027:Light; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D017319:Photosensitizing Agents / Q000494:pharmacology; D012235:Rhodamines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000528:radiation effects*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D014181:Transplantation Immunology / Q000528:radiation effects*; D014407:Tumor Cells, Cultured
D017319:Photosensitizing Agents; D012235:Rhodamines; C121365:4,5-dibromorhodamine 123