96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

DO-108
Identification of potential criteria for a successful Rituximab
salvage therapy in kidney allograft rejection
M . Dämmrich 1 , C . Blume 2 , C . Bockmeyer 1 , S . Immenschuh 3 , A . Schwarz 2 ,
D . Agustian 1 , V . Broecker 1 , H . Kreipe 1 , J . Becker 1
1 Hannover Medical School, Institute for Pathology, Hannover,
2 Hannover Medical School, Centre for Internal Medicine, Hannover,
3 Hannover Medical School, Institute for Transfusion Medicine, Hannover
Aims. Rituximab (anti-CD-20 antibody) is often used in kidney transplantation
to treat rejection refractory to standard treatment. Rituximab
therapy carries a risk for serious infectious complications and is not
effective in all cases. Therefore clinica, serological or histopathological
criteria to predict Rituximab response are most desirable. As a first step
for the identification of useful criteria we did a retrospective exploratory
analysis to identify criteria that were different between Rituximab responders
and non-responders.
Methods. 18 renal transplant recipients who received Rituximab (375 g/
m2 body surface, 1–2 courses after steroid bolus therapy, 15× combined
with up to 5 courses of plasmapheresis) for standard-therapy resistant
rejection were included in the study with their last biopsy before therapy.
10 were identified by terminal loss of transplant function as nonresponders,
8 as responders. Clinical, serological and histopathological
parameters were compared between both cohorts by Wilcoxon- or χ2
tests. P-values were regarded as descriptive in this retrospective analysis.
Results. At time of biopsy more of the Rituximab non-responders had
panel-reactive antibodies (>85%), and their serum creatinine before therapy
was higher. Among the histopathological criteria tubulitis was less
severe in responders. No significant differences were found for any of the
other clinical, serological or histopathological criteria.
Conclusions. In this retrospective exploratory study we identified lower
serum creatinine before therapy, the presence of panel- reactive antibodies
in more than 85% at time of biopsy, and a less severe Banff t-score as
possible criteria to predict responsiveness to Rituximab therapy. These
criteria need validation in future prospective randomized studies.
DO-109
Splenectomy and postconditioning with the sphingosine-1-phosphate
agonist FTY720 protect the myocardium against ischemia
reperfusion injury
D . Goltz1 , S . Huss2 , E . Ramadori1 , L . Diehl3 , R . Büttner2 , R . Meyer4 1 2 University of Bonn, Dept . of Pathology, Bonn, University of Cologne,
Dept . of Pathology, Köln, 3University of Bonn, Institute of Molecular Medicine,
Bonn, 4University of Bonn, Physiology II, Bonn
Aims. The pathogenesis of myocardial ischemia reperfusion injury
(MI/R) involves the inflammatory response of the innate immune system.
A modulation of this response could be a potential future target in
the management of the acute coronary syndrome. Recently, the spleen
has been proved an important origin of a Ly6-Cpos monocyte subset
that readily invades the injured myocardium upon ischemic damage.
We operated a murine myocardial ischemia reperfusion model in splenectomised
animals to reduce the invasion of phagocytic active immune
cells. In a second pharmacologic approach we applied the sphinosine-1phosphate
analogue FTY720 with reperfusion to interfere with the maturation
of monocytic derived macrophages. The aim of this study was
to evaluate the short and long term outcome of MI/R after modulation
the immune response.
Methods. In a murine closed-chest ischemia-reperfusion model, myocardial
infarct volume was assessed by TTC staining after 24 h of reperfusion
and by planimetric quantification of fibrosis on the Masson
stained specimen after 21 days of reperfusion in control animals, splenectomised
animals and FTY720 treated mice. Within the same interval,
cardiac function was evaluated by catheterisation using a Millar cathe-
ter. The immune response was characterised by FACS analysis in whole
heart specimens after 24 h.
Results. After 24 h of reperfusion, splenectomised animals and FTY720
treated animals revealed a significant reduction of infarct volume. The
invasion of monocytes, especially of Ly6-Cpos monocytes was significantly
reduced in splenectomised animals compared to the control
group. Moreover, the ratio of inflammatory macrophages to resident
macrophages was significantly smaller in the splenectomised group.
FTY720 treated animals showed an almost exclusive invasion by monocytes
within the remote myocardium. Functional data show a significantly
improved systolic cardiac function in both, the splenectomised
and the FTY720 treated groups compared to the control animal after
21 days of reperfusion. Quantification of the area of fibrosis, however,
revealed a trend towards reduced myocardial scarring in both target
groups, but the decline failed to reach a level of significance.
Conclusions. Both, splenectomy and postconditioning with FTY720 are
cardioprotective within 3 weeks after MI/R. In splenectomised animals,
this effect is due to a reduction of early invading monocytes. The mechanism
of FTY720 efficiency still warrants further investigation.
DO-110
Nestin expression in fetal and adult lungs vessels as well as vascular
tumors
S . Gerlach1 , G . Kristiansen1 , A .M . Müller2 1University Bonn Medical Center, Institute of Pathology, Bonn,
2University Bonn, Department of Pediatric Pathology, Bonn
Aims. The neural stem/progenitor cell marker Nestin is a class VI intermediate
filament protein. It is not only expressed by undifferentiated
central nervous system (CNS) cells during development and adult CNS
cells but various tumour cells as well as in injured and regenerating tissues,
indicating nestin as a marker for activated, migrating, proliferating
cells. Recently it has been described in proliferating endothelial cells
(EC). We were interested in any differences Nestin expression in fetal
and adult vessels as well as vascular tumors.
Methods. Endothelial Nestin and D2-40 expression was studied by immunolocalisation
in chorionic tissue from early abortions (n=5), fetal
(n=21) and adult (n=3) lungs, infantile hemangiomas (n=5) and angiosarcomas
(n=5).
Results. Although Nestin was expressed by EC of all blood vessels but not
lymphatic vessels there were differences concerning expression intensity.
In the first trimester, EC in chorionic and villous tissue as well as EC of
pulmonary veins, arteries and capillaries showed the same strong Nestin-positivity.
Starting in the second half of the second trimester Nestin
expression in venous EC began to fade, while arterial EC still showed a
strong staining. In lungs of neonates and adults the Nestin expression
was even weaker, although in arteries it was still stronger expressed than
in veins. In angiosarcomas Nestin was strongly expressed by the tumour
cells. EC of all infantile hemangiomas were clearly but in comparison to
angiosarcomas weaker stained.
Conclusions. The intermediate filament Nestin can be regarded as endothelial
marker expressed by vascular EC already during the first weeks
of life. As it is not expressed by lymphatic EC it can help discriminating
blood vessel endothelium from lymphatic endothelium. In accordance
with other endothelial markers like Angiotensin I converting enzyme it
is weaker expressed in adult pulmonary veins than adult pulmonary arteries.
The strong Nestin expression in fetal vessels – when compared to
EC of mature vessels or hemangiomas – corresponds to a strong Nestinpositivity
in malignant endothelial tumor cells. At present we analyse
the role of Nestin in colorectal cancer resp. its tumour vessels concerning
expression patterns in different stages of cancer.
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