Acute graft-versus-host disease: inflammation run amok?

Hematopoietic stem cell transplanta- tion (HSCT) has substantially fulfilled its promise as a curative therapy for hematopoietic disorders and some dis- orders of metabolism. More recently, it has been investigated for its potential in establishing tolerance for organ trans- plantation. In its typical application, conditioning steps involving cytotoxic radiation or chemotherapy are admin- istered first, after which some combi- nation of stem cells, lymphocytes, den- dritic cells, and other cells is infused into the recipient. In the treatment of malignant disorders, the goal is to erad- icate the cancer through a combination of cytotoxic injury and destruction of the malignancy by immunologic attack, a response described as the graft-versus- leukemia (GVL) effect. This approach is limited by (a) collateral tissue damage from the conditioning regimen, (b) immunological injury to normal tissues (graft-versus-host disease (GVHD)), and (c) the ability of the malignancy to survive this dual assault. substantial damage to the basilar layer of the skin, the intestinal crypts, and the portal area of the liver. Apoptosis of cells in these areas results in rash, mucosal denudation and subsequent diarrhea, and/or biliary stasis. In severe cases it can be fatal. One hint that helps explain the organ selectivity and some aspects of the pathophysiology of GVHD is the target organ distribution per se — these organs are all primary or secondary barriers to the environment. The functions of skin and gut are self- evident, and the liver's extensive reticu- loendothelial system reinforces the bar- rier function of the endotoxin-rich intestinal mucosa. While we refer to the GVH reaction as a "disease," it is better considered as a normal reaction of normal, donor lym- phocytes to what appears to the immune system to be a serious infec- tion. Thus, a reasonable framework in which to consider the induction of GVHD is that there is damage to the epithelium and endothelium by the conditioning regimen itself as well as by effects of the underlying disease. The injured tissues respond as if there were a serious infection, with the production of factors — cytokines, chemokines, and adhesion molecules, among others — that signal the immune system that infection or injury has occurred. The damaged tissues express antigens that are perceived as foreign by the immune system and are considered targets for elimination. The donor lymphocytes are in a milieu that fosters their direct attack on epithelia, causing tissue dam- age through perforin, granzyme B, and/or Fas/FasL interactions. They may also recruit other effector cells, such as granulocytes and macrophages (par- tially summarized in Figure 1). In addi- tion, the dysregulated production of inflammatory cytokines, such as TNF- α, IFN-γ, IL-1, and others, may cause direct tissue damage. Endotoxin may leak through these injured barriers, where it tends to fuel the response. Fur- ther injury to the barrier results in more release of endotoxin and exacerbation of the inflammation. Indirect support