Rapamycin promotes emergence of IL-10-secreting donor lymphocyte infusion-derived T cells without compromising their graft-versus-leukemia reactivity.
BACKGROUND
There are limited data examining the effects of pharmacological immunosuppression on the in vivo fate of donor lymphocyte infusions (DLI)-derived T cells, their function, and their antitumor efficacy.


METHODS
We addressed this question in a murine model in which DLI is given to stable mixed chimeras resulting in lymphohematopoietic graft-versus-host (LH-GVH) response. In this model, LH-GVH potency can be directly measured as the kinetics of conversion to full donor chimerism and can be correlated with associated graft-versus-leukemia (GVL) reactivity.


RESULTS
We found discordance in DLI-mediated LH-GVH reactivity depending on the timing of rapamycin (RAPA) administration. Delayed administration of RAPA in contrast to its early administration at the time of adoptive transfer did not interfere with conversion to full donor chimerism. Moreover, delayed administration of RAPA preserved the GVL reactivity of DLI. Analysis of the long-term chimeras showed that regardless of RAPA administration, adoptively transferred T cells mediating the LH-GVH response contribute minimally to the reconstitution of the peripheral T-cell compartment and exhibit profound hyporesponsiveness and decreased production of interleukin (IL)-2 on restimulation in vitro. However, we observed only in the RAPA-treated chimeras that the remaining hyporesponsive DLI-derived CD4+ T cells secrete large amounts of IL-10, a known immunoregulatory cytokine.


CONCLUSIONS
We conclude that delayed administration of RAPA after DLI does not interfere with their LH-GVH reactivity but promotes the emergence of IL-10-secreting DLI-derived CD4+ T cells that might contribute to the drug's known ability to promote bilateral donor host tolerance without interfering with GVL reactivity.
Durakovic
Nadira
N
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Radojcic
Vedran
V
Powell
Jonathan
J
Luznik
Leo
L
D000818:Animals; D002454:Cell Differentiation; D020544:Graft vs Leukemia Effect / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D023421:Models, Animal; D020123:Sirolimus / Q000494:pharmacology*; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000276:immunology
D007166:Immunosuppressive Agents; D016753:Interleukin-10; D020123:Sirolimus