Biology Reference
In-Depth Information
An early study using a rat haploidentical BMT model showed that increased
numbers of OX40
+
activated CD4
+
T cells were detected in peripheral blood,
spleen, and other target organs during acute GVHD
[85]
. Clinical studies
in allogeneic HCT also showed that OX40 was preferentially upregulated in
activated T cells from patients with acute as well as chronic GVHD
[83,86]
.
These published results suggest that OX40 might be a particularly useful
surface marker to assess the T-cell activation in GVHD. The increased pres-
ence of OX40
+
T cells in GVHD models leads to studying how OX40/OX40L
blockade could affect GVHD. Using OX40
−/−
mice as donors, OX40L
−/−
mice
as recipients, or the administration of a blocking anti-OX40L mAb similarly
reduced GVHD lethality independent of CD28 in a myeloablative MHC-
mismatched BMT model
[87]
. In contrast, agonistic anti-OX40 antibody
markedly increased the mortality in the same model. These results are con-
sistent with the data showing that OX40/OX40L interactions clearly acceler-
ate GVHD when it is preferentially mediated by CD4
+
T cells.
In a preclinical study,
in vitro
depletion of alloreactive OX40
+
T cells resulted
in a T-cell population that had reduced alloantigen-specific reactivity while
retaining T-cell specificity against third-party antigens including virus
(cytomegalovirus) and tumor antigens (WT1)
in vitro
[88]
. Collectively, all
the preclinical data suggest that interrupting the OX40/OX40L pathway
may be an interesting strategy to modulate GVHD in patients undergoing
allogeneic HCT.
205
4-1BBL/4-1BB pathway
4-1BB (CD137) is a member of the TNFR family and is rapidly expressed on
activated CD8
+
T cells and also on activated CD4
+
T cells with lower levels.
Its ligand, 4-1BBL, is a TNF family member and expressed on APCs such
as mature DCs, activated B cells, and macrophages
[89]
. When signaling
through the TCR is strong, 4-1BB engagement by 4-1BBL provides costimu-
latory signals to T cells independent of CD28. Although 4-1BB can activate
both CD4
+
and CD8
+
T cells
in vitro,
4-1BBL/4-1BB interaction preferentially
stimulates CD8
+
T cells, leading to expansion of CD8
+
T cells and increases
in their survival, cytolytic function, and IL-2 and IFN-γ production
[90]
.
By using 4-1BB
−/−
mice as donors or 4-1BBL
−/−
mice as recipients, the
GVHD lethality was largely reduced compared to wild-type (WT) groups.
In contrast, treatment of recipients with anti-4-1BB mAb augmented GVHD
lethality induced by either CD4
+
or CD8
+
T cells. Ligation of 4-1BB with its
specific mAb led to enhanced cytolytic function of CD8
+
T cells and CD8-
mediated GVL activity
in vivo
[91,92]
. Subsequently, other groups explored
the potential effect of 4-1BB blockade in the prevention of GVHD. The
administration of anti-CD137 mAb at the time of GVHD induction amelio-
rated the lethality of acute GVHD, but accelerated chronic GVHD
[93]
. The
treatment efficiently inhibited the expansion, IFN-γ production, and cyto-
toxic activity of CD8
+
T cells in both GVHD models. However, in chronic
GVHD, the number of CD4
+
T cells producing IL-4 was enhanced after treat-
ment, which might contribute to the exacerbation of chronic GVHD
[94]
.
In agreement, treatment of donor T cells with anti-4-1BBL
in vitro
reduced
GVHD and improved survival over a standard cyclosporin A + methotrexate
combination in an MHC-disparate BMT model
[95]
. Taken together, these
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