T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 200

of a nondepleting mAb specific for BTLA at the time of BMT permanently
prevented GVHD independent of its ligand HVEM. Furthermore, anti-
BTLA treatment led to the reduced expansion of Teffs relevant to naturally
occurring donor-derived Tregs and allowed for GVL effects as well as robust
responses to pathogens [66] . By applying an agonistic anti-BTLA mAb that
stimulates BTLA signal without blocking BTLA-HVEM interaction, Sakoda
et al. revealed that engagement of BTLA on T cells inhibited donor anti-
host T-cell responses and ameliorated GVHD after allogeneic BMT [182] .
Interestingly, expression of a BTLA mutant lacking an intracellular signal-
ing domain restored impaired survival of BTLA-deficient T cells, suggesting
that BTLA also serves as a ligand that delivers HVEM prosurvival signal in
donor T cells. Collectively, these studies suggest that to harness the function
of BTLA signals may be an important approach in the prevention of GVHD
while maintaining GVL responses and immunity to infection.

TNF/TNFR superfamily
CD40L/CD40 pathway

CD40 and CD40L (CD154) belong to the TNFR and TNF families, respec-
tively. CD40 is constitutively expressed at low levels on APCs including B
cells, dendritic cells, and monocytes, and its expression can be significantly
increased upon activation. CD40L is expressed on activated CD4 + T cells, a
small subset of CD8 + T cells, NK cells, and, in some cases, platelets. Ligation
of CD40 upregulates the expression of costimulatory molecules on APCs
(i.e., B7s) and contributes to an effective activation of T cells. In addition,
CD40/CD40L interactions enhance the production of proinflammatory
cytokines including IL-2, IL-12, and IFN-γ that further promote activation of
T and NK cells [67] . Blockade of CD4 + T cells using anti-CD40L mAb induces
tolerance of CD4 + T cells to host alloantigens ex vivo, and those tolerized T
cells are incapable of causing GVHD in vivo [68] . Tolerance induction via
ex vivo blockade of CD40/CD40L interaction resulted from incomplete acti-
vation of Teffs as well as the generation of potent Tregs [69] .

203

The role of the CD40/CD40L pathway in GVHD was first evaluated in non-
irradiated parent-into-F1 GVHD models, in which the administration of
anti-CD40L mAb (gp39) was able to reduce the occurrence of acute and
chronic GVHD [70] . In sublethally irradiated BMT models, administra-
tion of anti-CD40L mAb improved the GVHD caused by CD4 + T cells, but
not by CD8 + T cells, by inhibiting CD4 T-cell expansion and function [71] .
However, mechanistic studies revealed that treatment with anti-CD40L
not only blocks T-cell costimulation, but also selectively depletes acti-
vated T cells [72] . Interestingly, several studies have shown that blockade
of the CD40/CD40L pathway induces Tregs that may contribute to GVHD
inhibition [69,73] . The role of CD40 was investigated in the effect of an
agonistic anti-CD40 mAb on chronic GVHD in a nonirradiated parent-
into-F1 model. Administration of the mAb inhibited the production of
anti-DNA IgG1 autoantibody and the development of glomerulonephri-
tis. Ironically, the inhibition of chronic GVHD was due to the preven-
tion of donor CD8 + T-cell anergy through CD40 engagement, by which
activated CD8 + T cells deleted host CD4 + T cells and B cells involved in
autoantibody production. In addition, these activated donor CD8 + T cells