engleski

RESIDUAL HOST CHIMERISM AND PATTERN OF ANTIGEN EXPRESSION INFLUENCE THE FATE OF ADOPTIVELY TRANSFERRED ALLOGENIC T CELLS

Donor lymphocyte infusions (DLI) and allogeneic T cells specific for defined minor histocompatibility antigen (mHAg) are increasingly used in the treatment of relapsed malignancies after allogeneic BMT. However, the fate and function of adoptively transferred T cells are poorly understood. To evaluate the role of host chimerism, complete and mixed chimeras were constructed by transplanting DBA/2 mice (H-2d) with bone marrow (BM) from MHC-mismatched C56BL/6 (H-2b) donors after myeloablative and non-myeloablative conditioning, respectively. Three weeks later, both sets of chimeras received CFSE-labeled B6.SJL T cells, which uniquely express the CD45.1 allele. On day 6 and 10 after DLI administration, 86% and 93% of CD45.1+ T cells in mixed chimeras, respectively, and 41% and 63% of CD45.1+ T cells in full donor chimeras, respectively, underwent more than 7 divisions. Serial monitoring of CD45.1+ T cells in full donor chimeras revealed that 28% of these cells remain undivided for more than 20 days. To define the effect of targeted antigen tissue expression pattern on the fate of allogeneic antigen-specific T cells, we used transgenic mice with wide (HA104) or pancreas restricted (Ins-HA) expression of hemaglutinin (HA). TCR transgenic Clone 4 (CL4) mice, which contain H-2Kd restricted CD8+ T cells specific for HA peptide were used as a source of antigen specific T cells. HA104 or Ins-HA mice on BALB/c background underwent BMT from MHC-compatible B10.D2 donors, followed by DLI from TCR transgenic B10.D2-CL4 mice three weeks later. Differential expression of the Thy 1.1+ antigen on transgenic T cells was used for in vivo monitoring of their fate. Adoptively transferred TCR-specific transgenic CD8+ T-cells engrafted, expanded, and then sharply declined and became undetectable in the mice with wide distribution of targeted HA antigen. In contrast, transgenic T cells expanded but remained detectable for at least 30 days in the animals with pancreas restricted HA expression without causing diabetes. However, co-administration of vaccinia virus expressing HA together with transgenic T cells resulted in diabetes. In conclusion, residual host chimerism, targeted antigens pattern of expression and antigen-specific vaccinations have a potential to influence the fate of adoptively transferred allogeneic T-cells.

Donor Lymphocyte infusions; allogeneic T cells

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