Multilineage engraftment with minimal graft-versus-host disease following in utero transplantation of S-59 psoralen/ultraviolet a light-treated, sensitized T cells and adult T cell-depleted bone marrow in fetal mice.
Although engraftment following in utero stem cell transplantation can readily be achieved, a major limitation is the low level of donor chimerism. We hypothesized that a lack of space for donor cells in the recipient marrow was one of the primary reasons for failure to achieve significant engraftment, and that donor T cells could make space in an allogeneic mismatched setting. We found that 3 x 10(5) C57BL/6 (B6) naive CD3(+) cells coinjected with B6 T cell-depleted bone marrow (TCDBM) into 14- to 15-day-old BALB/c fetuses resulted in multilineage engraftment (median, 68.3%) associated with severe graft-vs-host disease (GvHD; 62 vs 0% with TCDBM alone). When 1.5 x 10(5) CD4(+) or CD8(+) cells were used, low levels of engraftment were seen vs recipients of 1.5 x 10(5) CD3(+) cells (2.4 +/- 1.1 and 6.6 +/- 3.9 vs 20.4 +/- 10.4%, respectively). To test the hypothesis that proliferation of T cells in response to alloantigen resulted in GvHD and increased engraftment, we pretreated naive T cells with photochemical therapy (PCT) using S-59 psoralen and UVA light to prevent proliferation. GvHD was reduced (60-0%), but was also associated with a significant reduction in engrafted donor cells (53.4 +/- 4.2 to 1.7 +/- 0.5%). However, when B6 T cells were sensitized to BALB/c splenocytes, treated with PCT, and coinjected with TCDBM, there was a partial restoration of engraftment (13.3 +/- 2.4% H2Kb(+) cells) with only one of nine animals developing mild to moderate GvHD. In this study we have shown that PCT-treated T cells that are cytotoxic but nonproliferative can provide an engraftment advantage to donor cells, presumably by destroying host hemopoietic cells without causing GvHD.
Bhattacharyya
Swati
S
Bone Marrow Transplant Division, Department of Pediatrics, University of California, San Francisco 94143, USA.
Chawla
Anjulika
A
Smith
Kristofer
K
Zhou
Yungui
Y
Talib
Sohel
S
Wardwell
Brian
B
Cowan
Morton J
MJ
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D002455:Cell Division; D002678:Chimera; D003114:Colony-Forming Units Assay; D003602:Cytotoxicity, Immunologic; D005260:Female; D005333:Fetus / Q000166:cytology / Q000276:immunology*; D011564:Furocoumarins; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous; D014466:Ultraviolet Rays
D011564:Furocoumarins; C118577:amotosalen