Delaney, Michael Paul (2001) Immunosuppressive drug interactions and resistance in mononuclear cells from renal transplant patients. MD thesis, University of Warwick.

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Abstract

Existing anti-rejection drug regimes are inadequate since patients receive drugs despite
serious side effects and poor response. New drugs are being developed
which ultimately may allow for prescribing of rational, patient-specific
immunosuppressive drug protocols. During this thesis the investigation of
lymphocyte responses from renal transplant recipients to the immunosuppressant
drugs Cyclosporin A (Cy A), FK506 and SDZ RAD were explored to understand
the variation in sensitivity of lymphocytes to Cy A and FK506, the development of
drug resistance, including resistance mechanisms, and the interactions between
FK506 and SDZ RAD.
Cy A and FK506 are substrates for P-glycoprotein (P-gp), the product of the
multidrug-resistance (MDR1) gene in man. A hypothesis established during this
thesis was that P-gp dependent mechanisms explain variations in lymphocyte
sensitivities to Cy A and FK50.
Lymphocytes from renal transplant recipients were assessed for their sensitivity to
Cy A and FK506 and subsequently for P-gp expression and functional activity by
flow cytometry. In further lymphocyte cultures the effect of the specific P-gp
inhibitor, PSC 833 on sensitivity was investigated. Finally, the effects of the
combination of FK506 and SDZ RAD in lymphocyte cultures were analysed.
Results demonstrate a wide range in lymphocyte sensitivity to both Cy A and
FK506, with the development of selective resistance to the drug used for
treatment. All patients demonstrated P-gp functional activity but P-gp expression
was not demonstrable. P-gp function did not account for the variation in
lymphocyte sensitivity. There was no evidence of antagonism of effect of SDZ
RAD in combination with FK506.
In conclusion, these results suggest that non-P-gp mechanisms account for
variations in lymphocyte sensitivity to Cy A and FK506. Combination therapy
with SDZ RAD and FK506 is unlikely to be antagonistic in future treatment
protocols.

Item Type:	Thesis or Dissertation (MD)
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Kidneys -- Transplantation, Lymphocytes, Immunosuppressive agents, FK-506 (Drug), Cyclosporine, Drug resistance
Official Date:	August 2001
Dates:	Date Event August 2001 Submitted
Institution:	University of Warwick
Theses Department:	Department of Biological Sciences
Thesis Type:	MD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Morris, A. G. (Alan George) ; Higgins, Rob
Sponsors:	Coventry Kidney Trust Fund
Extent:	xxiii, 191 p.
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/3703

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