B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 300

[7,28,59] . Thymic injury is not only important in its impairment of negative
selection of alloreactive conventional CD8 and CD4 T cells (Tcon), it also
interferes with the development of Tregs [60] .

When Treg and Tcon reconstitution was evaluated in patients during the
first year following myeloablative transplantation, two different patterns
emerged [7] . Tcon reconstitution occurs in two waves, the first comprising
the peripheral expansion of highly proliferative, memory T cells followed
by the second, thymic generation of naïve Tcon once thymic function
recovers. Treg reconstitution, on the other hand, is predominantly effected
by peripheral expansion even after thymic recovery; these Tregs are more
highly proliferative than their Tcon counterparts and largely have a mem-
ory phenotype throughout the first year following ASCT. Furthermore, Treg
proliferation is driven by CD4 T-cell lymphopenia. Despite a high prolifera-
tive index, however, Tregs remain low following transplantation, probably
because of an increased susceptibility to undergoing apoptosis, and thus
impaired Tcon reconstitution may lead to a relative deficiency of Tregs as
well. This is indeed the case, as patients with delayed Tcon recovery ini-
tially have similar numbers of Tregs compared with patients with early
Tcon recovery, but 9 months following transplantation Tregs fall in the for-
mer group despite a continual, albeit slow, recovery of Tcons. This pattern
of T-cell reconstitution is associated with a greater incidence of extensive
cGVHD, and the time of onset of cGVHD was generally after Tregs fell in
these patients. Treg deficiency, then, can be seen as a potential cause, and
consequence, of a failure to achieve T-cell tolerance and homeostasis post-
transplantation. The mechanism driving the loss of Tregs and their increased
susceptibility to undergoing apoptosis is unknown but one possibility may
relate to the fact that Treg telomerase activity is inversely correlated with the
development of extensive cGVHD and corresponds with shorter Treg telo-
mere length, decreased Bcl-2 expression and thus increased susceptibility
to undergoing apoptosis, and lower numbers of Tregs [25] .

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Interestingly, despite the fact that IL-2 is a known homeostatic cytokine for
Tregs, IL-2 levels did not differ between patients with and without cGVHD or
correlate with Treg recovery [23,24,26,27,61] . Administration of IL-2 to both
solid-tumor patients and patients following ASCT has resulted in expan-
sion of Tregs, and coadministration of IL-2 and donor lymphocyte infusion
enhanced that effect [23,27,61,62] . In vitro IL-2 results in the upregulated
expression of FOXP3 in CD4 + CD25 + T cells via STAT3 and STAT5 binding
to the first intron of the FOXP3 gene [62] . The use of IL-2 as a treatment for
cGVHD is discussed in the last section of this chapter.

B cells and chronic graft-versus-host disease

T cells are essential for the pathogenesis of cGVHD, but increasing evidence
points toward a role for B cells in this disease as well. Deposition of IgM and
complement has been demonstrated at the dermal/epidermal junction in
patients with cGVHD [63] . In a mouse model of MHC-mismatched cGVHD,
donor B cells were found to be necessary for the development of cGVHD
[14] . In humans, at least some of these B cells produce known autoantibod-
ies [64] . Following sex-mismatched ASCT, Y-encoded mHAs elicit specific
antibody responses, and the presence of these alloantibodies correlates