B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 302

obliterans, liver involvement with perivascular infiltration surrounding the
bile ducts and extending into the parenchyma, infiltration and inflamma-
tion of the oral mucosa and salivary glands, thymic and splenic destruction,
and colonic involvement. Moreover, collagen deposition was increased
in all involved organs but most notably the lung and liver compared with
control mice who received T-cell-depleted bone marrow-derived stem cells
alone. Lung and liver pathology was remarkable for increased CD4 T-cell
and B220 B-cell infiltration, but not that of CD8 T cells, as well as immu-
noglobulin deposition in the cGVHD mouse model compared with control
mice. Incubation of tissue from a naïve syngeneic host mouse with sera
from transplanted animals confirmed that these immunoglobulins were
reactive against host tissue antigens. Grafts from B-cell-deficient donor
mice and mice with hypo-IgG-secreting B cells did not result in bronchi-
olitis obliterans. These transplants did result in lung and liver lymphocyte
infiltration and inflammation but without bronchiole or bile duct destruc-
tion or immunoglobulin deposition, demonstrating that immunoglobu-
lin deposition is not responsible for inflammation but instead may be
responsible for in situ tissue injury. Blockade of germinal center formation
with mouse LTβR-Ig fusion protein in mice transplanted according to the
cGVHD model also did not result in bronchiolitis obliterans; liver fibrosis
was likewise decreased. When sera from these mice that had received the
LTβR-Ig fusion protein was incubated with tissue from a naïve, syngeneic
host there was diminished peribronchiolar and perivascular deposition in
the lung and liver, respectively. This model thus provides evidence for an
antibody-dependent mechanism of B cells in cGVHD pathogenesis.

306

B-CELL-ACTIVATING FACTOR AND THE SURVIVAL OF AUTO- AND ALLOREACTIVE
B CELLS IN CHRONIC GRAFT-VERSUS-HOST DISEASE

What is different, then, between patients who do and do not develop anti-
body responses following transplantation is unknown, much as the mecha-
nisms of loss of humoral tolerance in autoimmune diseases remain to be
elucidated. The similarities between autoimmune diseases and some mani-
festations of cGVHD, however, allow us to learn from the experience with
rheumatology. B-cell-activating factor (BAFF) is an important regulator of
B-cell homeostasis and specifically promotes the survival of transitional
and mature B cells. Elevated levels of BAFF have previously been implicated
in the pathogenesis of autoimmune diseases, and antibodies targeting
BAFF have recently been approved for the treatment of SLE [81] . At nor-
mal levels, BAFF preferentially promotes the survival of antigen-activated
B cells through activation of the alternate NF-κB pathway and enhanced
expression of antiapoptotic genes such as Bcl-2, Bcl-X L , and Mcl-1 [82-84] .
Autoreactive B cells, on the other hand, appear to require a greater thresh-
old of BAFF-BAFF receptor (BAFFR) signaling for survival, perhaps owing to
downstream signaling changes that occur as a result of more intense B-cell
receptor (BCR) signaling. When BAFF levels are limiting, antigen-activated
B cells preferentially survive, and only when BAFF levels are in excess is
BAFF-BAFFR signaling able to prevent apoptosis of autoreactive B cells and
promote the development of autoimmunity [85] .

BAFF has previously been shown to play a critical role in B-cell reconstitu-
tion following myeloablative conditioning [82,86,87] . BAFF levels are high