Impact of the conditioning regimen - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 163

ch 8

Impact of the conditioning
regimen

E Holler
Department of Haematology/Oncology, University Medical Center, Regensburg, Germany
R Storb
Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

In pathophysiology of transplant-related complications, especially graft-
versus-host disease (GVHD), a first step is activation of the recipient epithe-
lial target tissues like skin or gut, which is usually associated with damage
of epithelial stem cells, subsequent breakdown of the epithelial barrier and
resulting inflammation. Conditioning is thought to be the most important
cause of this process, and we will review both the evidence and the mecha-
nisms involved.

165

First evidence for a role of conditioning in
pathophysiology of GVHD
Animal studies

A direct link between conditioning-related damage and inflammation and
GVHD had been postulated by Xun and colleagues [1,2] who showed induc-
tion of TNF and other inflammatory cytokines by total body irradiation
(TBI) and linked it to more severe GVHD. Later on, Hill and colleagues [3,4]
used two different doses of TBI and clearly demonstrated stronger induc-
tion of gut damage and proinflammatory cytokines by the higher dose
resulting in more lethal GVHD.

Clinical studies

First clinical evidence for a role of intensity conditioning came from the early
studies on pathogenesis of interstitial pneumonia, where TBI delivered with-
out appropriate lung shielding contributed to increased and more severe
lung damage. A direct link between intensity of conditioning and GVHD was
made by Clift and colleagues [5,6] where patients receiving a higher dose of
TBI experienced less relapse but a higher incidence of acute GVHD. How-
ever, another possible explanation for some of the data in the paper by Clift
et al. is that toxicities associated with the higher TBI dose often precluded
full dosing of drugs aimed at GVHD prevention. Since that time, intensity of
conditioning and/or use of TBI at all during conditioning has been identified