Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 227

cells, which naturally tend to differentiate along a Tc1 pathway during acute
GVHD [61] , operate through Fas ligand cytolysis and IFN-γ secretion, which
primes monocytes and macrophages for proinflammatory cytokine secre-
tion that is a hallmark of the more distal, “cytokine storm” phase of acute
GVHD (see Chapter 16). Further evidence for a Th1-predominant patho-
genesis emanates from experiments using donor T cells which multiply
deficient in the Th2 cytokines IL-4, IL-5, IL-9, and IL-13: recipients of such
Th2 cytokine quad knockout T cells had increased GVHD [62] .

However, several results caution against viewing the natural history of acute
GVHD as a strict Th1-driven process and indicate a role for both Th1 and
Th2 cells, including observations that: (1) STAT4-deficient T cells restricted
in Th1 differentiation maintain some GVHD potential [63] , (2) specific dele-
tion of IL-2- or IL-4-secreting donor T cells can reduce GVHD [64] , and (3)
absence of IFN-γ actually worsened GVHD, whereas absence of IL-4 was
protective against GVHD [65] .

Recent murine data using donor T cells rendered double deficient for key
polarizing cytokines further confirmed that multiple T-helper subsets can
contribute to the natural history of acute GVHD [66] . In this study, Th1,
Th17 and Th2 effector subsets each contributed to GVHD but mediated dif-
ferent degrees of GVHD severity (Th1 and Th17 > Th2) and different GVHD
target tissue distributions (shift of immunity to Th1 and Th17 cells was
associated with gut GVHD; shift to Th2 cells was associated with pulmonary
GVHD). In another recent example, donor T cells with combined deficiency
in T-bet and ROR-γ had reduced Th1- and Th17-type reconstitution and
increased Th2- and Treg-type reconstitution post-transplant which, inter-
estingly, resulted in abrogation of GVHD with preservation of a GVT effect
[67] . Therefore, a model can emerge whereby immune space generated
during conditioning for allogeneic transplantation allows for expansion of
available T-helper cell subsets, the balance of which will help determine the
outcome of transplantation responses.

230

There has been a recent and substantial revision to the classification of clin-
ical chronic GVHD [68] . And, in experimental models, there has been simi-
lar evolution in terms of an understanding of chronic GVHD pathogenesis,
including the potential role of the Th1/Th2 subsets. In early models, which
emphasized de novo generation of chronic GVHD in a manner that arguably
does not mimic the clinical scenario, chronic GVHD was primarily viewed
as a Th2-dominant process that was thus reciprocal to acute GVHD; for
example, Th2-driven murine chronic GVHD was reversed by IL-12, which
shifted immunity toward a Th1 type and transformed GVHD into an acute
phase [58] .

More recently, however, alternative models of experimental chronic GVHD
have been developed, which may better reflect the biology of GVHD as it
occurs in the clinic. Specifically, the Drobyski group has developed a model
whereby acute GVHD is first generated, with subsequent adoptive transfer
of such “allo-experienced” T cells into immune-deficient syngeneic murine
hosts [69] ; this model, in addition to displaying a sequential acute-into-
chronic process, allows experimental assessment of chronic GVHD as an
autoimmune disease, which primarily characterizes the clinical presen-
tation. Using this model and donor T cells genetically deficient in various