B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 297

A major concern in treating, or perhaps more importantly in preventing,
cGVHD stems from its clear association with the graft-versus-leukemia
(GVL) and graft-versus-tumor (GVT) effects of transplantation. As both pro-
cesses are at least in part driven by antigen-specific cellular and humoral
immune activation in the setting of immune intolerance, suppressing one
has the potential to, and in many cases does, have an impact on the other.
Understanding the differences between the two processes, then, is critical to
separating them after transplantation and improving transplant outcomes.

Chronic graft-versus-host disease
Distinctions between acute and chronic graft-versus-
host disease

cGVHD differs from aGVHD in its presentation, typical time of onset post-
transplantation, and pathogenesis. aGVHD typically occurs in the first 100
days post-transplantation, although late-onset aGVHD is a currently rec-
ognized diagnosis, as the clinical picture of the disease is more informative
with regard to pathogenesis than the time of onset [4] . A diagnosis of late-
onset aGVHD requires the absence of National Institutes of Health (NIH)
criteria for the diagnosis of cGVHD. aGVHD is the result of donor T-cell acti-
vation by host antigen-presenting cells in the setting of an inflammatory
environment [10] . Its pathogenesis is discussed in great detail throughout
this topic but, in brief, both CD4 and CD8 T cells are activated and trafic
to the skin, gastrointestinal tract, and liver, where they cause direct tissue
damage and destruction through direct cytotoxicity and cytokine-mediated
injury. Trafficking to target organs is mediated by the expression of specific
adhesion molecules, and the elaboration and secretion of specific cytokines
such as interleukin-1 (IL-1), IL-6, IL-12, interferon-γ (IFN-γ), and tumor
necrosis factor-α (TNF-α) result in a predominately type 1 (Th1) immune
response [11,12] . The clinical presentation of aGVHD is one of a diffuse
maculopapular rash, cholestatic liver injury, anorexia/food intolerance,
diarrhea and abdominal cramping, and immune suppression. Prophylactic
immunosuppression with agents that target T-cell activation has resulted in
decreased rates of aGVHD but not cGVHD.

301

In contrast, cGVHD is marked by inflammation and fibrosis, with tis-
sue destruction involving the skin, gastrointestinal tract, liver, lung, eye,
and salivary and lacrimal glands. cGVHD is not simply the end result of
inflammation caused by aGVHD, although a history of aGVHD is a signifi-
cant risk factor for the development of cGVHD [13] . Instead it appears to
have a unique pathogenesis that is currently being elucidated. cGVHD has
previously been considered a disease marked by type 2 (Th2) cellular and
humoral immune responses. In some mouse models of cGVHD, both CD4
T cells and B220 B cells, but not CD8 T cells, are necessary for the develop-
ment of the disease [14] . When a mouse model of aGVHD was compared
to a model of cGVHD, spleen cells isolated from the latter were found to
secrete more immunoglobulin in culture than spleen cells isolated from
the former [15-17] . It should be noted that many of these models do not
accurately recapitulate the clinical manifestations of cGVHD seen in
humans; while sclerodermatous skin and Sjogren-like changes occur in