Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 232

in vivo: polarized T cells generated ex vivo in rapamycin, particularly the
CD4 + Th2 cell subset, had a marked degree of expansion and persistence
in vivo and were highly efficacious in the prevention of rejection. Second,
RR-Th2 cells manifested a multifaceted resistance to apoptosis that was
associated with marked alteration of the Bcl-2 family gene expression,
including upregulation of antiapoptotic Bcl-xl and downregulation of
proapoptotic Bim and Bid [85] . In sum, these data indicate that Th2 cells
demonstrate potential for the promotion of engraftment with reduced
GVHD and indicate that Th2 adoptive cell therapy efforts should focus on
the manufacture of T-cell products with an enhanced capacity to persist
in vivo, such as T cells exposed to high-dose rapamycin.

Clinical transplantation and the Th1/Th2 paradigm
Overview

Relative to the significant depth and breadth of information pertaining to
Th1/Th2 cross-regulation at the levels of transcriptional mechanism and
experimental transplantation models, there is a paucity of information
regarding the potential role of this biology in the natural history of clini-
cal transplantation responses and a general lack of tools required for the
transplant practitioner to manipulate this biology for therapeutic benefit.
State-of-the-art data do not appear to exist in terms of defining the clinical
allograft content of bona fide Th1 or Th2 cells, including limited informa-
tion relating to transcription factor analysis. Nonetheless, it has been known
for a long time that the precursor frequency of clinical allograft T cells capa-
ble of secreting IL-2 or IL-4 correlated with increased or decreased acute
GVHD, respectively [92,93] ; on a broad level, these data are consistent with
the Th1/Th2 principles discovered in experimental models. Further assess-
ment of the Th1/Th2 paradigm in the clinic has been relatively limited in its
scope, as efforts to define post-transplant immune reconstitution have, in
general, focused on serum cytokines (which may not reflect T cell events)
or have primarily favored analysis of FOXP3 + Treg reconstitution without
analysis of T-bet + or GATA-3 + events.

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Prior efforts to modulate the Th1/Th2 balance after clinical
transplantation

Because G-CSF shifted donor T cells to a Th2 phenotype and reduced
murine GVHD [94] , the clinical use of G-CSF prior to peripheral blood or
marrow harvest can be considered as an attempt to shift post-transplant
immunity toward a Th2 phenotype for reduction in GVHD. In the clinical
setting, grafts harvested after donor treatment with G-CSF were indeed
somewhat Th2 biased [95] ; however, similar rates of GVHD were observed
whether the marrow inoculum was harvested with or without donor G-CSF
treatment [96] . There are several reasons why treatment of donors or post-
transplant recipients with cytokines or growth factors may not be able to
potently modulate the Th1/Th2 balance, including toxicity of therapy
before a desired biologic effect can be achieved (administration of high-
dose cytokines is associated with significant toxicity) and differential effects
of cytokines on T cells relative to other cell populations such as NK cells or