B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 306

cGVHD and disease relapse, respectively [99] . Similarly, in vitro stimula-
tion of peripheral blood mononuclear cells isolated from chronic lympho-
cytic leukemia (CLL) patients following ASCT with CLL cells allowed for the
isolation of T-cell clones that were subsequently tested against recipient
and donor cells, including recipient CLL cells [100] . All of the patients who
had a response to their transplant developed T-cell clones that were spe-
cific for antigens expressed by CLL cells; these included both mHAs and
nonshared tumor-specific antigens; no anti-CLL T-cell clones were iden-
tified in patients who failed to respond to transplant. As outlined previ-
ously, experience with T-cell-depleted grafts supports the importance of
cellular immunity in GVL/GVT; while depleting stem cell grafts of T cells
has resulted in decreased rates of GVHD, it has also resulted in increased
rates of infection and relapse [49-53] . While cGVHD is thought to be associ-
ated with a Th2 immune response marked by elevations in IL-4, IL-5, and
IL-10, GVL/GVT has been associated with a Th1 response in mice [101,102] .
Manipulation of stem cell grafts in leukemic mouse models of ASCT such
that the graft was skewed toward a Th1 or Th2 phenotype resulted in a sur-
vival advantage of leukemic mice transplanted with a Th1 graft; cell mixing
experiments showed that Th2 immune cells decreased the GVL effect of
the Th1 graft [102] . Altering the cytokine environment in the graft, post-
transplantation, or for the treatment of GVHD offers a potential means
of separating GVL/GVT from GVHD. However, animal and some human
experiments involving the blocking of inflammatory cytokines such as IL-1
or TNF-α or administration of IL-2, IL-4, and IL-10 have been associated
with mixed results for the treatment of GVHD and limited evidence of an
effect on GVL/GVT [9,103-108] .

310

Coordinated B- and T-cell responses in the graft-versus-
tumor effect

Donor T cells can enhance anti-tumor immunity in two ways. First, donor T
cells contribute to the elimination of the host immune system. In patients
with advanced cancer, the recipient's immune system is markedly impaired
and often tolerant of the patient's own tumor cells. This occurs as a result of
the malignancy itself and/or as a result of prior treatments that the patient
has received [109] . Subsequently, enhanced immune reconstitution and
recovery of a broad T-cell repertoire have been associated with improved
outcomes, including disease control, post-transplantation [110] . Second,
the development of donor T cells that recognize antigens expressed on
residual tumor cells can directly eliminate these cells in the recipient after
transplant. Previous studies have shown that many of the antigenic targets
of these donor T cells are mHA derived from genetic polymorphisms that
distinguish recipient from donor. When these mHA are widely expressed in
recipient tissues as well as normal hematopoietic cells and leukemia cells
(shown schematically in Figure 14.2 ), donor T cells targeting these antigens
contribute to the development of GVHD as well as GVL. When the expres-
sion of specific mHAs is restricted to normal and malignant hematopoietic
cells in the recipient, donor T cells targeting these antigens can result in
conversion to complete donor chimerism as well as GVL, but T cells specific
for these mHA are less likely to also cause GVHD. Importantly, tumor cells
also express unique antigens that are not expressed in normal tissues of the