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these models, there is a lack of pulmonary, hepatic, or other gastrointesti-
nal pathology and there is a gain of other pathologies including glomerulo-
nephritis, polyarthritis, and periarteritis, more consistent with a lupus-like
disorder. What has been discovered from these imperfect models, however,
is that immunoglobulin secretion is the result of host B-cell activation by
donor CD4 T cells recognizing major histocompatibility complex (MHC)-
restricted antigens
[18]
. Further characterization of the immunoglobulins
secreted showed that there was a significant increase in IgE; again CD4
but not CD8 T cells were necessary for IgE production, and blocking IL-4
with a monoclonal antibody resulted in abrogation of IgE secretion
[19]
.
Quantification of mRNA for various cytokines from spleen cells from these
mice demonstrates higher expression of IL-4 and lower expression of IL-10,
IFN-γ, and MIP-1α in the cGVHD compared with the aGVHD model
[20]
.
T cells from mice with cGVHD were found to produce high amounts of IL-4
but low amounts of IL-2 and IFN-γ compared with control mice
[21]
. IFN-
γ secretion could be restored following administration of a monoclonal
antibody against IL-10, which was found to be more highly expressed by
spleen cells from mice with cGVHD. Host B cells in this model were found to
have increased cell surface expression of MHC class II antigens but this was
decreased following treatment with antibodies to IL-4. In addition to activa-
tion of host B cells, antibody production, and enhancement of MHC class
II expression leading to perhaps greater antigen presentation, Th2 cyto-
kines such as IL-4, IL-5, and IL-13 are significantly associated with fibro-
genesis that is characteristic of organ damage in cGVHD
[22]
. Finally, the
relative deficiency of IL-2 production by CD4 T cells in examples of cGVHD
may relate to the decrease in Treg numbers that is observed in these mod-
els, as IL-2 is a known homeostatic cytokine for these cells
[9,23-28]
. Thus
a model emerges in which the failure to develop T-cell tolerance leads to
the persistence of allo- and autoreactive T cells following ASCT, a cytokine
environment in which there is activation of B cells, with resultant antibody
production and enhanced antigen presentation, and ultimate propaga-
tion of antigen-specific immune responses with direct tissue destruction
by antibody/complement- and cytokine-mediated pathways (
Figure 14.1
).
It should be noted, however, that this cytokine profile has not been con-
sistently observed in humans
[29,30]
. Moreover, almost all patients with
cGVHD have complete donor chimerism and few, if any, remaining host
hematopoietic cells are present in these patients.
302
T cells and chronic graft-versus-host disease
Early evidence for the survival of alloreactive lymphocytes against non-
HLA, or minor histocompatibility antigens (mHAs), came from experi-
ments done following HLA-matched sibling donor transplants in patients
with aplastic anemia or leukemia
[31]
. Sibling donors who were HLA-A and
HLA-B identical to the patient and whose lymphocytes did not react to host
leukocytes in a mixed leukocyte culture (MLC) were used, and post-trans-
plant lymphocytes (of donor origin) were tested for reactivity against cells
from host, donor, and unrelated individuals in MLC. Post-transplant donor-
derived lymphocytes were reactive against host cells in 64% of patients who
developed cGVHD, whereas this was found in only 8% of patients without
cGVHD. Likewise, these post-transplant lymphocytes were more frequently
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