Impact of the conditioning regimen - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 164

as a risk factor for GVHD in several trials. In a recent CIBMTR analysis, the
complex interaction of intensive conditioning and graft source was high-
lighted, as GVHD was always highest in myeloablative regimens including
TBI when peripheral blood stem cells were used as the stem cell source [7] .

The cumulative incidences of both acute and chronic GVHD among patients
given allogeneic hematopoietic cell transplants after minimal-intensity and
minimially toxic conditioning regimens are comparable to those among
patients given high-intensity conditioning, suggesting other mechanisms
can contribute to GVHD. A possible mechanism could be the presence after
hematopoietic cell transplantation (HCT) of host antigen-presenting cells
that initiate GVH reactions. Median times of onset of GVHD are generally
later in these patients, which could be due to the difference in mechanisms
initiating GVH reactions [8,9] .

Mechanisms of increased GVHD
Role of target cells: epithelial damage and toxicity

EXPERIMENTAL EVIDENCE

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It has been a long debate why specific epithelial tissues such as skin and gut
are the predominant targets of GVHD, and this can be discussed in the con-
text of conditioning and GVHD: It is unlikely that these tissues have a higher
susceptibility of their stem cells to cytotoxic drugs or irradiation. However,
both targets are direct interfaces between our bacterial environment, or as
it is now called, our microbiome and epithelia, and one possible expalana-
tion is that epithelial damage allows translocation of bacterial ligands and
penetration of bacteria across damaged barriers, thereby inducing increased
inflammation, thus also supporting specific alloreactions. The role of bacte-
ria in epithelial GVHD was first demonstrated by van Bekkum who showed
absence of GVHD in germfree mice [10,11] . Later on, the interaction was
explained by translocation of LPS, as LPS-resistant donor mice develop
less GVHD and protection of translocation by strategies enhancing epi-
thelial integrity such as use of keratinocyte growth factor or interleukin 11
protected from GVHD [12-15] . In the meantime, it is clear that there are
complex interactions between intestinal microbia, innate and adaptive
immune reactions [16] , and that conditioning disrupts several mechanisms
of homeostasis required for tolerance against commensal bacteria in the
intestinal tract. Only recently, the role of direct damage to epithelial stem
cells and Paneth cells has been reemphasized, as it has been shown that
GVHD further enhances conditioning-induced stem cell damage and loss
of Paneth cells, producing antibacterial peptides [17,18] .

CLINICAL EVIDENCE

The direct link between epithelial damage and more severe GVHD in patients
is less well established, partially explained by the difficulties in quantifying
epithelial damage by non-invasive approaches. Measuring gastrointestinal
leakage as an indirect marker of epithelial barrier damage, Johannsen et al.
postulated a direct link [19] , and studies using the combination of TBI and
etoposide as a highly intense conditioning regimen suggested more severe