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The effect of intraportal mannitol on the short-term in vivo distribution of radiolabelled A-LAK cells in rats

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Zhou, Jianhua (1994) The effect of intraportal mannitol on the short-term in vivo distribution of radiolabelled A-LAK cells in rats. Research Master thesis, University of Tasmania.

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Abstract

The effectiveness of adoptive immunotherapy of cancer using LAK cells
and IL-2 depends on the accumulation of transferred effector cells at the
tumour sites. In vitro LAK cell have been demonstrated to have broad
cytotoxic activity to a wide variety of tumour cells in a non-major-histocompatibility
complex-restricted manner, and independent of the
presence of tumour specific antigens. LAK cells have now been used
effectively in a small number of human trials. The effective delivery of
these cells to the tumour site in vivo is one of the main aspects of this type
of immunotherapy that requires further investigation. Conventional
systemic infusion has shown a limited migration pattern of LAK cells. In
this study the degree of entrapment of LAK cells in organs following local
infusion has been determined. The large size and rigidity of LAK cells
may be one mechanism which restricts the distribution of these cells. In
addition, in this study the effect of mannitol, a hyperosmotic agent which
increases the space between vascular endothelial cells, on the uptake of
intraportal LAK cells into liver has been determined.
A-LAK cells are obtained by culture of N.W.P. lymphocytes with IL-2. In
this study A-LAK cells were characterised by typical morphologic
appearance, cell surface phenotype, and cytotoxic specificity. Purified A-LAK
cells were morphologically large granular lymphocytes, 67%-90% of
which showed the surface marker phenotype of NK/LGL cells (OX8). The
population contained few pan-T cells (only 4.0-6.5% of cells expressing
OX19). No B cell surface marker lg was detectable in the A-LAK cell
population. These cells showed high ability to lyse YAC-1 and P-815
cultured tumour target cells in 4h 51Cr-release cytotoxic assays. At an
Effector:Target ratio of 40:1 A-LAK cells lysed 70% P815 and 100% YAC-1
cells.
After labelling A-LAK cells with 51Cr, the effect of intraportal infussion of
30% mannitol on the distribution of intraportally infused A-LAK cells in
liver was studied. The trafficking studies were carried out in three
groups. In Group 1, 51Cr labelled A-LAK cells were systemically infused
through the tail vein of rats as a control group. In Group 2 and Group 3,
A-LAK cells were infused into syngeneic rats through the portal vein
without or following prior portal infusion of 30% mannitol. Two hours
after LAK cell administration the rats were sacrificed and the radioactivity
in liver, lung, spleen, blood, MLN, kidney and brain were measured to
determine the distribution of A-LAK cells to these organs.
The results showed that intraportal mannitol was associated with an
increased percentage of LAK cells in the liver compared with regionally
infused LAK cells without mannitol (54% vs 24%; P<0.0005). The
administration of intraportal mannitol was also associated with increased
distribution of A-LAK cells into the brain (0.26% vs 0.08%; P<0.05) and
MLN (0.05% vs 0.02%; P<0.05). There was no significant increase in
uptake of A-LAK cells in lung (8.39% vs 6.01 %), spleen (1.00% vs 0.98%),
or kidney (1.44% vs 1.78%) following intraportal mannitol.
There was no significant increase of the A-LAK cell distribution to the
liver by regional infusion without mannitol (24% vs 16%). Systemic
injection gave greater A-LAK uptake into lungs (15.65%) than portal
injection (6.05%, P=0.05). There was no significant differences of cell
distribution in spleen, MLN, kidney and brain by these two routes of
infusion.
These results showed that mannitol has the effect of increasing the
distribution of LAK cells into the liver. Augmentation of LAK cell
accumulation in the liver may help to enhance the tumouricidal activity of
these cells to hepatic metastases. The results of this thesis suggest area_s for
further investigation into the effect of mannitol and other agents on A-LAK
cell uptake into the liver following regional infusion.

Item Type: Thesis (Research Master)
Keywords: Cell-mediated cytotoxicity, Cancer, Cells, Cancer cells
Copyright Holders: The Author
Copyright Information:

Copyright 1994 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).

Additional Information:

Includes bibliographical references (leaves 83-94). Thesis (M.Med.Sc.)--University of Tasmania, 1995

Date Deposited: 04 Feb 2015 23:23
Last Modified: 24 Aug 2016 04:31
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