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STAT signaling pathways, chronic GVHD was characterized as a disease
mediated by Th1 and Th17 subsets that avoided Treg cell inhibition. These
experimental findings are consistent with the biology of clinical chronic
GVHD of the oral cavity, which appears to be mediated by T-bet
+
Th1/Tc1-
type cells
[70]
.
Therapeutic models using Th1/Th2 cell adoptive transfer
Adoptive transfer experiments using wild-type yet purposefully polarized
donor T cells have found that Th1 and Tc1 cells mediate increased GVHD
relative to Th2 and Tc2 cells and determined that Th2-type cells can actively
downregulate GVHD induced by donor T cell inocula
[71-74]
. These results
therefore stand somewhat in agreement with the previously described
results in natural history models that used cytokine-, signaling-, or tran-
scription factor-deficient donor T cells. In the recent models that we have
evaluated,
ex vivo
manufacture and polarization of T cells occur in a poly-
clonal manner with subsequent antigen-driven clonal expansion occurring
in vivo
after adoptive transfer
[74]
; this therapeutic strategy thereby frag-
ments the normal process of T-cell activation whereby T-cell polarization
and specificity are generated simultaneously.
231
In the setting of transplantation for therapy of malignant disease, it is
essential to also determine the effect of any given anti-GVHD strategy on
GVT effects. In experiments that involved the adoptive transfer of
ex vivo
-
generated, cytokine-polarized murine T cells, we found that a clean dissec-
tion of GVT effects from GVHD was not possible using Th1 versus Th2 cells.
That is, in a murine model of leukemia, the anti-GVHD effect of adoptively
transferred Th2 and Tc2 cells significantly blunted the post-transplant
anti-tumor effect
[73]
. In marked contrast, adoptive transfer of
ex vivo
-gen-
erated Th1 and Tc1 cells resulted in potent GVT effects at the expense of
lethal GVHD. Similarly, in a murine model of metastatic breast carcinoma,
adoptive transfer of Th1/Tc1 cells resulted in potent GVT effects and lethal
GVHD; in contrast, Th2/Tc2 cell recipients had greatly reduced GVHD but
eventually died from insufficient GVT effects
[74]
. Such difficult dissec-
tion of GVHD and GVT effects reflects the shared biology of these complex
transplantation responses (reviewed in
[75]
).
Experimental models using
ex vivo
rapamycin
As summarized in
Figure 11.2
, we have evaluated the role of
ex vivo
rapa-
mycin for modulation of the post-transplant Th2/Th1 balance. First, rapa-
mycin (Sirolimus) has a distinct mechanism of action and more complex
immune modulation effects relative to the calcineurin inhibitors cyclospo-
rin A and FK506 (Tacrolimus), which operate primarily through inhibition
of T-cell mRNA transcription (reviewed in
[76]
). Rapamycin inhibition of
mTOR results in the blunting of a myriad of cell-surface receptor signals,
including cytokine, costimulatory, and nutritional pathways; as a result,
downstream signals are silenced, including protein translation (through
the 4EBP1 pathway), protein phosphorylation (through the p70S6 kinase
pathway), and cell cycle progression. Our initial rationale to test rapamy-
cin
ex vivo
for Th1/Th2 modulation strategies included observations that
rapamycin administration after murine allogeneic bone marrow transplant
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