B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 296

the varied clinical manifestations of this disease in humans. Moreover, until
recently, the definition and grading of cGVHD were not uniform among
studies [6] . As such, current standard therapies are relatively nonspecific
and broadly immunosuppressive, and their efficacy is disappointing.

Failure of donor T cells to develop tolerance to recipient tissues following
transplantation appears to be central to the pathogenesis of this disease.
Why some patients develop such tolerance and do not develop cGVHD
while others do not and go on to develop cGVHD is not understood and
warrants further investigation. Various factors contribute to the inability to
develop T-cell tolerance, including impaired thymic deletion of auto- and
alloreactive T cells as a result of thymic damage by acute graft-versus-host
disease (aGVHD) and/or conditioning. Inadequate or delayed recovery of
regulatory T cells (Treg) has also been demonstrated in cGVHD. Finally,
abnormal levels of homeostatic cytokines during reconstitution can also
contribute to impaired reconstitution of T and B cells. The consequences
of this lack of T-cell tolerance are multifold: specific cytokine profiles that
promote the activation of effector immune cells, persistent activation of
auto- and alloreactive T cells and deficiencies in Tregs, and aberrant sur-
vival of auto- and alloreactive B cells that result in both antibody-inde-
pendent and antibody-dependent pathology ( Figure 14.1 ). Understanding
these potential causes and effects of immune intolerance has informed
new therapeutic approaches to this disease, including T-cell depletion,
administration or inhibition of specific cytokines and cytokine receptors,
and B-cell-directed therapies. Furthermore, a recurring theme from studies
that examine immune reconstitution patterns following ASCT implicates
alterations in the homeostatic patterns of various B- and T-cell subsets in
patients who develop cGVHD, and approaches to restoring homeostatic
balance are being investigated [7-9] . These approaches, in isolation and in
combination, have the promise to improve the prognosis of this disease for
the first time in decades.

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FIGURE 14.1
Schematic of the pathogenesis of chronic graft-versus-host disease (cGVHD). As a result of thymic damage, cytokine imbalance, impaired immune reconstitution,
and regulatory T-cell deficiency, patients who develop cGVHD fail to achieve T-cell tolerance, which results in the persistence of an abnormal cytokine profile, auto- and
alloreactive T cells and the survival of auto- and alloreactive B cells. The end results of this immune dysregulation are inflammation and infiltration of target tissues,
antibody deposition, and fibrosis.