B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 299

reactive with donor cells if they were from patients with cGVHD compared
with patients without cGVHD (32% vs 8%). This suggested that cGVHD was
in part a consequence of immune intolerance and the survival of allore-
active lymphocyte clones specific to host antigens. In mouse models of
cGVHD following HLA-matched ASCT, CD4 T-cell clones have been identi-
fied that respond to MHC class II antigens that are expressed by both the
donor and the recipient [32] . In addition to an impairment in peripheral
tolerance, these clones also appear to have escaped negative selection by
the thymus, perhaps related to thymic damage that occurs following cer-
tain conditioning regimens as well as a result of aGVHD [33,34] . This has
been shown to be the case in some mouse models of cGVHD in that thymic
dendritic cells were noted to be absent in mice with aGVHD, subsequently
allowing for the persistence of donor-derived CD4 T cells reactive against
host alloantigens [35,36] .

The differential rate of cGVHD observed following matched-related and
matched-unrelated donor transplantation suggests that there are immuno-
logically important mHAs that have yet to be identified but are genetically
distinct or polymorphic at greater frequencies among unrelated donor and
recipient pairs. A more detailed discussion of mHAs can be found in Chap-
ter 3. Only approximately 40 mHA epitopes have been described for which
post-transplant reactive T-cell clones have been identified [37] . One-third
of these epitopes belong to a small subset of proteins encoded by genes
on the Y chromosome and become significant following transplants from
a female donor to a male recipient of ASCT. These H-Y antigens are recog-
nized by female donor CD4 and CD8 T cells and cellular responses to these
epitopes are associated with cGVHD [38-42] .

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Further evidence for the critical role that T cells play in the pathogenesis of
cGVHD comes from the results of stem cell graft T-cell depletion studies.
Methods of T-cell depletion include the use of narrow- and broad-spectrum
anti-T-cell antibodies, the anti-CD52 monoclonal antibody alemtuzumab,
elutriation, and lectins [43-48] . The use of anti-thymocyte globulin as part
of the conditioning regimen has a similar effect. In general, T-cell deple-
tion of both matched related and unrelated donor grafts has resulted in
decreased rates of acute and chronic GVHD but increased rates of infection
and relapse such that overall survival is unchanged [49-53] . Thus, it appears
that removing donor T cells from the graft is an effective strategy to decrease
the risk of GVHD, but not without increasing the risk of relapse due to a pre-
sumed loss of a GVL effect.

Regulatory T cells and chronic graft-versus-host disease

CD4 + CD25 + FOXP3 + Tregs are a mature T-cell subset that plays a major
role in peripheral immune tolerance, and deficiencies of Tregs have been
implicated in autoimmunity [54,55] . The importance of Tregs in maintain-
ing immunologic balance and tolerance following ASCT was first demon-
strated in mouse models: graft Treg depletion resulted in enhanced cGVHD
rates, whereas increasing graft and peripheral Tregs resulted in an abroga-
tion of this disease [56-58] . In humans, diminished numbers of peripheral
Tregs is associated with cGVHD, and peripheral depletion of Tregs following
myeloablative ASCT correlates with the development of extensive cGVHD