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

• Published in: The Journal of immunology (1950) 2002-12, Vol.169 (11), p.6133-6140
• Main Authors: Bhattacharyya, Swati, Chawla, Anjulika, Smith, Kristofer, Zhou, Yungui, Talib, Sohel, Wardwell, Brian, Cowan, Morton J
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation - adverse effects; Bone Marrow Transplantation - methods; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Division; Chimera; Colony-Forming Units Assay; Cytotoxicity, Immunologic; Female; Fetus - cytology; Fetus - immunology; Furocoumarins; Graft Survival; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Immune Tolerance; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Pregnancy; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transplantation, Homologous; Ultraviolet Rays
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.11.6133

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.