Graft-vs-leukemia activity and graft-vs-host disease induced by allogeneic Th1- and Th2-type CD4+ T cells in mice.
BACKGROUND
The transfer of allogeneic lymphocytes contained in a hematopoietic stem cell graft confers an immune-mediated antileukemic effect, termed the graft-vs-leukemia (GVL) effect. Graft-vs-host disease (GVHD), the most detrimental complication of allogeneic BMT, largely resides within the same lymphocyte population. Therefore, separation of GVL- and GVH-reactions is a long-standing goal of experimental studies dealing with allogeneic transplantation of hematopoietic stem cells.


METHODS
The objective of the current study was to assess the potential of Th1- and Th2-type CD4+ T cells in mediating GVHD and GVL effects in a fully allogeneic murine transplant model. BALB/c (H-2d) mice were given a dose of A20 (H-2d, B-cell leukemia) cells two days prior to lethal total body irradiation (TBI) and transplantation of fully mismatched (C57BL/6, H-2b) T-cell depleted (anti-Thy1.2, CD90) bone marrow (TCD-BM) cells. Graded numbers of either unmanipulated, Th1- or Th2-polarized highly enriched CD4+ donor type T cells (10(6) or 10(7)) were administered 2 h posttransplant. Infusion of 10(6) of unmanipulated, Th1-, or Th2-primed CD4+ T cells resulted in moderate GVHD-related mortality (40%, 50%, 10%) and significantly improved long-term survival (50%, 45%, 46% surviving the observation period of 120 days) as compared to animals receiving TCD-BM alone (18%).


RESULTS
The administration of 10(7) unmanipulated or Th1-type CD4+ T cells given shortly after transplantation led to death of all mice within 50 days due to fatal acute GVHD. In contrast, the adoptive transfer of 10(7) Th2-primed CD4+ T cells resulted in significant improvement of long-term survival (80%) compared to the TCD-BM group. This powerful GVL effect was associated with a substantially lower incidence of lethal acute GVHD (10%) if compared to the results of transplantation of Th1-type CD4+ T cells.


CONCLUSIONS
These results demonstrate that allogeneic Th2-type CD4+ T cells given post BMT can induce GVL effects in a cell-dose-dependent manner without increasing the risk of severe acute GVHD.
Zeis
M
M
2nd Department of Internal Medicine, University of Kiel, Kiel, Germany. mzeis47@hotmail.com
Uharek
L
L
Hartung
G
G
Glass
B
B
Steinmann
J
J
Schmitz
N
N
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease / Q000378:metabolism / Q000628:therapy*; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation; D007942:Leukemia, Experimental / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018417:Th1 Cells / Q000637:transplantation*; D018418:Th2 Cells / Q000637:transplantation*; D014184:Transplantation, Homologous