Biology Reference
In-Depth Information
FTY, a compound derived from the fungus,
Isaria sinclairii
, binds sphingosine
1-phosphate receptors (SIPRs) with high affinity, which can result in immu-
nomodulation by sequestering lymphocytes within secondary lymphoid
organs
[97]
. Using three different mouse models of major MHC-mismatched
transplantation, Taylor et al. demonstrated that FTY could extend the mean
survival time of mice with GVHD
[98]
. By imaging GFP
+
T cells after trans-
plantation, it was observed that FTY-treated mice had a transient increase in
donor effector accumulation in mesenteric lymph nodes and Peyer's patches
at day 4. Furthermore, fewer donor T cells were found in other inguinal and
axillary lymph nodes, spleen, and gut-associated lymphoid tissue at days 4
and 7. Interestingly, numbers of donor T cells in the liver and lung were unaf-
fected by FTY treatment. Furthermore, it was found that a combination ther-
apy of CD4
+
CD25
+
Tregs with FTY could have an additive effect in improving
survival. Thus, this study indicated a potential for FTY in ameliorating GVHD
by sequestering effector T cells and could have potential in clinical applica-
tion to GVHD, particularly in combination with Treg.
There have been many studies indicating that CD4
+
CD25
+
Treg can be potent
suppressors of GVHD (see section “Exploring GVHD with bioluminescence”
above). The importance of the adhesion molecule, CD62L (L-selectin), in
the ability of Tregs to suppress GVHD was clearly demonstrated in a study
directly comparing the effects of CD62L expression on Tregs an allogeneic
transplantation
[99]
. CD25-depleted eGFP
+
CD4
+
effector T cells were trans-
planted into lethally irradiated recipients and imaged 1 week after trans-
plantation. At this time point, allogeneic CD4
+
T-cell signals were very bright
in spleen, lymph nodes and Peyer's patches. However, if mice also received
CD62L
hi
Tregs, the GFP signal from the CD4
+
T cells was only slightly higher
than in syngeneic control mice. However, if CD62L
lo
Tregs were used, there
was no significant inhibition of CD4
+
T cells in lymphoid organs. At 2 weeks
after transplantation, GFP signal continued to increase in GVHD controls
and GVHD mice treated with CD62L
lo
Tregs, but signals in CD62L
hi
Treg-
treated mice remained dim, again approximating signal levels in syngeneic
control mice. These data concur with other reports on the importance of
CD62L expression for Treg function
in vivo
, and suggest that strategies to
optimize CD62L expression on Tregs should improve their efficacy.
71
Nuclear imaging (PET/SPECT)
Positron emission tomography (PET) utilizes positron-emitting radio-
nucleotide labels (tracers) that are short-lived and created immediately
before use via neutron bombardment of normal chemicals with a cyclotron
beam. When a positron is emitted from the tracer and hits an electron in
the tissue, the resulting matter-anti-matter annihilation produces two pho-
tons of gamma rays which travel in opposite directions, and are detected
by gamma ray detectors, which convert the radiation to visible light, and
photomultiplier tubes which convert the light into electrical signals. Single-
photon emission computed tomography (SPECT) is very similar to PET, but
it uses radioactive substances which directly emit single gamma rays and
have much longer half-lives. The principal strengths of nuclear imaging
methods are that they have high sensitivity, are highly quantitative, have
excellent tissue penetration and, unlike BLI, can be readily translated to the
Search WWH ::
Custom Search