Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 236

nearly all patients had predominant donor T-cell and myeloid cell elements.
Conversion of mixed chimerism in T-Rapa cell recipients was relatively
safe, as there were no cases of transplant-related mortality and only 4/40
recipients (10%) developed acute GVHD. In addition, some patients with
chemotherapy-refractory hematologic malignancy have remained in sus-
tained complete remission. Finally, we observed that the post-transplant
ratio of GATA-3 + to T-bet + T cells in T-Rapa recipients was similar to the
ratio observed in the T-Rapa cell clinical products [100] , suggesting that the
manufactured product helped dictate the post-transplant ratio of Th2 and
Th1 cells. In sum, these data provide a basis for further evaluation of T-Rapa
cells, which represent a mix of minimally differentiated Th2 and Th1 cells,
for the promotion of alloengraftment and mediation of GVT effects without
increased GVHD.

Future directions/unanswered questions

Recent history has seen remarkable progress in the identification and
further elucidation of molecular mechanisms that contribute to the gen-
eration and regulation of the Th1/Th2 and Tc1/Tc2 subsets. Perhaps just
as remarkable, experimental transplantation researchers have “kept up
with the times” and have applied these T-cell immunology principles for
an improved understanding of acute GVHD, chronic GVHD, GVT effects
and graft rejection. This experimental modeling has become increasingly
sophisticated and mechanistic, with state-of-the-art studies in experimen-
tal transplantation now including the evaluation of T cells simultaneously
deficient in multiple cytokines, various STAT transcription factors, or T-bet
and GATA-3 transcription factors. And, perhaps as a sign that investigations
are addressing a more translational agenda, an increasing number of stud-
ies are being performed in human-into-mouse xenogeneic transplantation
models. Key current and future research foci may include evaluation of: (1)
whether newly identified transcription factors that control T-cell cytokine
phenotype (such as Runx3 and eomesodermin) will confirm and extend
the understanding of Th1/Th2 regulation of transplantation responses; (2)
whether novel therapeutics that target STAT signaling pathways or canoni-
cal transcription factors can be utilized to modulate the Th1/Th2 balance
in vivo for therapeutic gain (for example, allow for a Th1-mediated potent
GVT effect with subsequent Th1 cell conversion to a less pathogenic T-helper
cell subset); and (3) whether new methods of ex vivo T cell manipulation of
donor T cells can be utilized to more optimally control the in vivo Th1/Th2
balance to address disparate transplantation goals (for example, mediation
of potent GVT effects in the advanced, refractory tumor-bearing state). On
these last two points, there should be healthy debate and investigation as
to whether attempts to modulate the Th1/Th2 balance are optimally per-
formed using in vivo modulation or ex vivo graft engineering approaches,
or perhaps a combination of the two methods.

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In contrast to the relatively rich understanding of the role of the Th1/Th2
paradigm in the modulation of transplantation responses, an understand-
ing of this biology at the clinical stage is relatively rudimentary, with many
questions currently unanswered. Even more sobering, there have been
only a few attempts to purposefully control the Th1/Th2 balance after