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with the development of cGVHD
[65,66]
. Specifically, half of men tested fol-
lowing ASCT with a female donor had developed antibodies against DEAD
box RNA helicase Y (DBY) by 6-12 months following transplantation
[66]
.
When this analysis was expanded to include antibody responses against
five Y-encoded proteins, 52% of male ASCT patients with female donors
developed antibodies against at least one Y-encoded antigen and 31% of
such patients developed antibodies to two or more such antigens
[65]
. The
time to development of an antibody response ranged from 4 to 12 months
in these patients and persisted throughout follow-up. These results were
the same regardless of the stem cell source or type of pretransplantation
conditioning. Most importantly, the development of antibodies to H-Y anti-
gens was significantly associated with the development of cGVHD (odds
ratio 15.5,
p
< 0.0001), and disease relapse correlated with the absence of
both cGVHD (
p
< 0.0001) and an H-Y antibody response (
p
< 0.001). Allo-
reactive CD4
+
T cells appear to be necessary for the development of these
antibodies
[38]
. Screening peripheral blood mononuclear cells from a male
patient following transplantation from a female donor against a panel of
DBY peptides revealed the presence of a CD4 T-cell clone reactive against a
single 19-mer DBY peptide restricted by HLA-DRB1*1501. This T-cell clone,
however, was also reactive against the X homolog peptide and responded
equally to peptide presented by both male and female dendritic cells. There
was also an antibody response to DBY, suggesting that the specificity for the
immune reaction can be is rendered by the B- and not the T-cell response.
305
MECHANISMS OF B-CELL PATHOGENESIS IN CHRONIC GRAFT-VERSUS-
HOST DISEASE
The pathogenicity of auto- and alloantibodies after ASCT, however, remains
unproven, as transfer of antibodies between mice with and without cGVHD
has not consistently transferred the disease phenotype in all models
[67,68]
.
Rituximab as a treatment for cGVHD is discussed in greater detail in the last
section of this chapter, but its efficacy further supports a role for B cells in
the development of cGVHD
[69-77]
. Its effect can be seen before a decrease
in antibody titers would be expected
[71]
. These observations suggest that
B cells contribute to cGVHD through both antibody-dependent and anti-
body-independent mechanisms. In addition to mechanisms mediated by
specific antibodies, these include direct antigen presentation, the produc-
tion of cytokines that modulate the intensity and type of immune response,
and the development of immunoregulatory B-cell subsets that usually
suppress T-cell responses
[78]
. Evidence for B cells as antigen-presenting
cells in cGVHD comes from experiments that have demonstrated increased
B-cell responsiveness to CpG-DNA in patients with, compared to patients
without, cGVHD
[79]
. B cells from patients with cGVHD have enhanced
expression of the costimulatory molecule CD86 after Toll-like receptor 9
(TLR9) stimulation compared with controls, making them more effective in
activating cognate T cells
[79]
.
A mouse model has recently been described that more closely recapitulates
the cGVHD phenotype seen in humans
[80]
. Following conditioning with
cyclophosphamide and total body irradiation, these mice receive T-cell-
depleted bone marrow-derived stem cells in combination with allogeneic
spleen cells. They develop lung dysfunction consistent with bronchiolitis
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