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molecule (memTNF), and formation of soluble TNF requires cleavage of
the memTNF molecule by TNF-α converting enzyme (TACE)
[41]
. Both sol-
uble and memTNF signal via either of two ubiquitously expressed TNFR,
TNFRI (p55) and TNFRII (p75), which are also utilized for LTα3 signaling
[42]
. The results of signaling through these two receptors are markedly
different. TNFRI (p55) possesses an intracellular death domain (DD) and
therefore can directly induce apoptosis via the activation of caspase-3 and/
or -8, whereas TNFRII does not possess this DD. The intracellular portion of
the TNFRII instead contains a TNFR-associated factor-interacting protein,
with ligation leading to translocation of nuclear factor-κB and inflamma-
tion
[43]
(this paper is an important review of the mechanisms involved in
TNF superfamily signaling). There is some evidence, however, that TNFRII
can contribute to cytotoxicity via ligand passing
[44]
.
Soluble lymphotoxin (initially described as TNF-β) is one of the core mem-
bers of the TNF superfamily of signaling molecules. The first discovery of
the cytokine reported it as a cytolytic factor produced by lymphocytes
[45]
.
Like TNF, it is known to promote both apoptosis and proliferation of T cells,
along with inflammatory responses
[46]
. Of note, while LTα3 can signal via
both TNFR, there is evidence that its dominant action is via TNFRI
[47]
.
364
PRECLINICAL EVIDENCE FOR THE IMPORTANCE OF TNF
Mouse models of GVHD have established a role for TNF in GVHD patho-
genesis. Preclinical data generated using donor mice deficient in TNF and/
or the TNFR confirm this as an important ligand-receptor pathway
[48]
,
predominantly in GVHD of the GIT and skin
[49]
. The expression of the
p55 TNFR on host tissue is required for the full penetrance of GVHD
[48]
.
Since LTα3 is also generated during GVHD, and utilizes the same signaling
pathways as TNF, it is reasonable to assume that this molecule also induces
many of the effects that had previously been attributed solely to TNF.
When TNF was studied using a well-established parent-into-F1 model of
GVHD with the addition of the P815 (recipient derived) mastocytoma
tumor line, blockade of soluble TNF using the TNFR:Fc construct (a sol-
uble TNFRp75 molecule conjugated to an Fc construct, which therefore
neutralizes TNF and LTα) resulted in increased leukemia mortality
[36]
. In
this study, it was again demonstrated that TNFR p55 is crucial for mainte-
nance of CTL generation and GVL activity. This series of experiments also
utilized alternative conditioning regimens, including a cyclophosphamide
(Cy)-based pretreatment and a Cy/total body irradiation (TBI) combination
therapy that utilized only low-dose TBI. With Cy/TBI therapy, treatment of
recipients with TNFR:Fc made no difference to GVHD outcome compared
with control therapy
[36]
, highlighting the role of pretransplant damage
with intensive TBI doses to disease pathogenesis.
To address the roles of soluble and membrane-bound TNF, mice were gen-
erated that lacked TACE and thus were capable of producing only a mem-
brane-bound form of the TNF molecule. Data were generated using these
transgenic animals to separate the effects of the soluble and membrane-
bound forms of the molecule of donor origin in both GVHD and GVL exper-
iments
[50]
. The results obtained indicated that it was soluble TNF playing
a key role. The capacity of donor T cells to secrete soluble TNF significantly
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