T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 203

data indicate that the 4-1BBL/4-1BB pathway can contribute to the devel-
opment of GVHD significantly. Interestingly, a single injection of an agonis-
tic anti-CD137 mAb at the onset of chronic cutaneous GVHD reversed skin
fibrosis, ulceration, and alopecia, ultimately improving general health con-
ditions [96] . The reversal is associated with markedly reduced CD4 + T-cell
cytokines and increased apoptosis of donor CD4 + T cells in a Fas-dependent
manner. These data indicate that the anti-CD137 mAb has a therapeutic
effect on cutaneous GVHD by removing donor CD4 + T cells that cause cuta-
neous GVHD.

CD137 has also been evaluated as a target molecule to selectively deplete
alloreactive T cells in vitro [97] . Compared with other activation-induced
antigens, CD137 showed a superior performance based on a consistently
low baseline expression and a rapid upregulation following alloantigen
stimulation. The frequency of alloreactive CD8 T cells can be reduced to
a median of 9.5% compared with undepleted control populations. The
allodepleted T-cell subsets maintained significant anti-tumor and antiviral
CD8 responses, suggesting a promising approach that infusion of leukemia/
tumor-reactive CD8 T-cell lines followed by CD137 depletion may confer
strengthened GVL reactivity without causing GVHD in HLA-haploidentical
and single allele mismatch settings.

206

CD30L/CD30 pathway

CD30, a member of the TNFR family, is expressed on activated T cells, NK
cells, and B cells. Its ligand, CD30L (CD153), is expressed on activated T
cells, resting B cells, and macrophages. Early in vitro studies led to the
classification of CD30 as a T-cell “costimulatory receptor” based on obser-
vations that immobilized CD30-specific mAb or CD30L-transfected cells
enhance the proliferation of human T cells in response to suboptimal
stimulation via TCR [98] . The physiological relevance of these early find-
ings is not clear because anti-human or anti-mouse CD30L mAbs do not
appear to block APC-dependent T-cell proliferation and/or function in a
variety of in vitro systems. As CD30 is expressed on T cells rather late after
in vitro activation, it is possible that CD30/CD30L interactions occur-
ring relatively late after antigen encounter promote T-cell survival and/
or establishment of strong memory responses [99] . CD30 signaling reg-
ulates peripheral T-cell responses, controlling T-cell survival and down-
regulating their cytolytic capacity. Although initial analysis suggested a
role for CD30 in Th2 development, studies have shown a role for CD30 as
a T-cell-costimulatory molecule involved in Th1, Th2, and Th17 immune
responses [100,101] .

The role of the CD30/CD153 interaction in GVHD has been demon-
strated in murine BMT models using a neutralizing anti-CD153 mAb,
CD30 −/− donor mice, and CD153 −/− recipient mice. Recipients receiving
CD30 −/− donor T cells had longer survival compared to those receiving
WT T cells in an MHC class II-disparate BMT model. Similarly, admin-
istration of a blocking anti-CD30L mAb improved survival in mice
after receiving MHC-disparate CD4 + T cells [102] . Thus, blockade of the
CD30/CD153 pathway represents a new approach for preventing CD4 +
T-cell-mediated GVHD.