Transplantation of Polarized Type 2 Donor T Cells Reduces Mortality Caused by Experimental Graft-Versus-Host Disease1

Abstract

Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage.

Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation.

“…Second, the addition of IL-4 to primary MLC of donor T cells and host stimulator cells results in T cell polarization and a reduction in acute GVHD when these cells are used as the donor T cell inoculum (16). However, GVHD target organs are not protected long-term by this approach (32). Third, the use of G-CSF for the mobilization of donor cells also induces Th2 polarization and reduces GVHD (54), which may help to explain the lower incidence of severe acute GVHD observed after transplantation using G-CSF mobilized stem cells (55).…”

“…Previous studies have shown that Th2 polarization alone does not always prevent GVHD target tissue damage despite improved survival (32). We therefore studied the long-term effects of IL-11 on two GVHD target organs, the GI tract and liver (33).…”

G-CSF-primed haploidentical marrow transplantation without ex vivo T cell depletion: an excellent alternative for high-risk leukemia

“…18 Treatment that induces Th2 response reduces GVHD. 19 G-CSF polarizes T cell differentiation from Th1 to Th2 type cells and induces Th2 responses, with the production of IL-4 and IL-10. 20 Tayebi et al 21 compared phenotypic and functional properties of lymphocytes from bone marrow or PBSC donors after G-CSF treatment in a randomized study.…”

G-CSF mobilized vs conventional donor lymphocytes for therapy of relapse or incomplete engraftment after allogeneic hematopoietic transplantation

“…28 In several experimental models, donor Th2 cells have a decreased potential to induce aGVHD. [29][30][31][32][33][34] G-CSF-mobilized grafts have been associated with reduced severity of aGVHD apparently via disruption of cytokine cascades involved in the development of aGVHD. Importantly, however, G-CSF-mobilized grafts maintain their GVL effects through a perforin-dependent pathway.…”