Impact of the conditioning regimen - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 166

Activation and elimination of antigen-presenting cells

In our current understanding of pathophysiology of GVHD, host antigen-
presenting cells (APCs) are most critical in intitiation of donor T-cell acti-
vation [36] . It is not entirely clear whether conditioning-related release
of inflammatory cytokines results from activation of epithelial cells or
hematopoietic cells, but several studies suggest direct activation of mac-
rophages and APCs by conditioning. Several studies suggested that host
APCs or corresponding cells are required for induction of GVHD [37] ,
which would suggest that the kinetics of elimination of APCs by differ-
ent conditioning regimens might have an impact on GVHD. Until now,
the data on elimination of APCs by conditioning are conflicting: Clini-
cal data [38,39] suggest less rapid elimination at least of skin APCs by
reduced intensity approaches. Although one would expect more and
more pronounced GVHD in this setting, this is not confirmed in experi-
mental and clinical trials. The effect on APCs may be counterbalanced
by less intense tissue damage and translocation of microbial patterns, as
discussed before, but recent studies in addition suggest a shift of donor
T-cell activation towards regulatory T cells in the presence of reduced
intensity conditioning [40] .

168

Controversies and alternative explanations

The exact contribution of conditioning to pathophysiology of GVHD
remains controversial, as it may not be directly involved but contribute
as one of several mechanisms to inflammation which seems to be cru-
cial. Even the exact nature of inflammation needs further clarification as
a recent study from Shlomchik´s group excluded a crucial role of classical
TLR- and IL-1-dependent pathways [41] . However, the pathways result-
ing in inflammasome activation are much more differentiated then previ-
ously expected, and step by step analysis of the different inflammasomes
is needed [42] .

Thus, it may well be that conditioning and conditioning-related inflammation
have a major impact on kinetics of GVHD but not on its incidence. In trials
aiming at specific elimination of APCs such as in a prophylactic UVB irra-
diation trial to eliminate host Langerhanns cells the major finding was a
shift of GVHD from early to delayed onset without a major impact on the
incidence and severity [43] . The group of Gratwohl also challenged the con-
cept of conditioning-related inflammation and GVHD, as they compared
allogeneic transplantation immediately after BEAM conditioning with a
delayed transplantation to allow recovery from conditioning-related dam-
age and did not observe any difference [44] .

Further explanations may conflict with the concept: There may be broad
overlap of early conditioning-related toxicity and GVHD in standard and
full intensity conditioning, and this may be more relevant for skin than for
gut GVHD. In addition, indirect effects have to be considered, as patients
receiving full intensity conditioning with subsequent toxicity may either
receive reduced doses of immunosuppressive prophylaxis, especially
methotrexate, or experience altered pharmacokinetics due to hepatic
toxicity.