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P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection.
Transplantation. 2004 Jun 15; 77(11):1699-706.T

Abstract

BACKGROUND

Modulation of P-glycoprotein (P-gp) activity in graft-infiltrating T cells may alter their susceptibility to immunosuppression.

METHODS

P-gp activity was measured by rhodamine efflux in T-cell subsets from bronchoalveolar lavage (BAL) of five healthy volunteers and 27 lung allograft recipients. The effect of T-cell activation on P-gp activity was modeled by stimulation of peripheral blood mononuclear cells with staphylococcal enterotoxin B.

RESULTS

Most BAL T cells expressed memory-effector markers. Patients had a lower proportion of CD4 T cells (P = 0.005), whereas control subjects had CD4-to-CD8 ratios similar to peripheral blood. In controls, basal P-gp activity was greatly increased in both CD4 (35% P-gp active) and CD8 (63%) lung T cells compared with peripheral T cells. Basal P-gp activity was elevated in patient BAL T cells but was lower than control BAL activity (CD4, P = 0.07; CD8, P = 0.03). Lung T cells from transplant patients had modest (CD4) or marked (CD8) increases in substrate-induced P-gp activity compared with normal lung, indicating that P-gp was not irreversibly inhibited. Patients with acute cellular rejection (ACR) had reduced P-gp activity in CD4, but not CD8, BAL T cells compared with patients without ACR (P = 0.004). To determine the relationship between T-cell activation on P-gp modulation, P-gp activity was measured in staphylococcal enterotoxin B-stimulated peripheral blood mononuclear cells. P-gp activity was abrogated in CD71 cycling cells but remained high in a persistent but minor population of resting naive T cells.

CONCLUSIONS

Lung T cells have increased in vivo P-gp activity and therefore may eliminate substrate drugs, resulting in local resistance to immunosuppressive therapy. However, P-gp function is reduced during T-cell activation, providing a window of susceptibility to treatment during ACR.

Authors+Show Affiliations

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. donnenbergad@msx.upmc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15201669

Citation

Donnenberg, Vera S., et al. "P-glycoprotein Activity Is Decreased in CD4+ but Not CD8+ Lung Allograft-infiltrating T Cells During Acute Cellular Rejection." Transplantation, vol. 77, no. 11, 2004, pp. 1699-706.
Donnenberg VS, Burckart GJ, Zeevi A, et al. P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection. Transplantation. 2004;77(11):1699-706.
Donnenberg, V. S., Burckart, G. J., Zeevi, A., Griffith, B. P., Iacono, A., McCurry, K. R., Wilson, J. W., & Donnenberg, A. D. (2004). P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection. Transplantation, 77(11), 1699-706.
Donnenberg VS, et al. P-glycoprotein Activity Is Decreased in CD4+ but Not CD8+ Lung Allograft-infiltrating T Cells During Acute Cellular Rejection. Transplantation. 2004 Jun 15;77(11):1699-706. PubMed PMID: 15201669.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft-infiltrating T cells during acute cellular rejection. AU - Donnenberg,Vera S, AU - Burckart,Gilbert J, AU - Zeevi,Adriana, AU - Griffith,Bartley P, AU - Iacono,Aldo, AU - McCurry,Kenneth R, AU - Wilson,John W, AU - Donnenberg,Albert D, PY - 2004/6/18/pubmed PY - 2004/7/14/medline PY - 2004/6/18/entrez SP - 1699 EP - 706 JF - Transplantation JO - Transplantation VL - 77 IS - 11 N2 - BACKGROUND: Modulation of P-glycoprotein (P-gp) activity in graft-infiltrating T cells may alter their susceptibility to immunosuppression. METHODS: P-gp activity was measured by rhodamine efflux in T-cell subsets from bronchoalveolar lavage (BAL) of five healthy volunteers and 27 lung allograft recipients. The effect of T-cell activation on P-gp activity was modeled by stimulation of peripheral blood mononuclear cells with staphylococcal enterotoxin B. RESULTS: Most BAL T cells expressed memory-effector markers. Patients had a lower proportion of CD4 T cells (P = 0.005), whereas control subjects had CD4-to-CD8 ratios similar to peripheral blood. In controls, basal P-gp activity was greatly increased in both CD4 (35% P-gp active) and CD8 (63%) lung T cells compared with peripheral T cells. Basal P-gp activity was elevated in patient BAL T cells but was lower than control BAL activity (CD4, P = 0.07; CD8, P = 0.03). Lung T cells from transplant patients had modest (CD4) or marked (CD8) increases in substrate-induced P-gp activity compared with normal lung, indicating that P-gp was not irreversibly inhibited. Patients with acute cellular rejection (ACR) had reduced P-gp activity in CD4, but not CD8, BAL T cells compared with patients without ACR (P = 0.004). To determine the relationship between T-cell activation on P-gp modulation, P-gp activity was measured in staphylococcal enterotoxin B-stimulated peripheral blood mononuclear cells. P-gp activity was abrogated in CD71 cycling cells but remained high in a persistent but minor population of resting naive T cells. CONCLUSIONS: Lung T cells have increased in vivo P-gp activity and therefore may eliminate substrate drugs, resulting in local resistance to immunosuppressive therapy. However, P-gp function is reduced during T-cell activation, providing a window of susceptibility to treatment during ACR. SN - 0041-1337 UR - https://www.unboundmedicine.com/medline/citation/15201669/P_glycoprotein_activity_is_decreased_in_CD4+_but_not_CD8+_lung_allograft_infiltrating_T_cells_during_acute_cellular_rejection_ L2 - https://doi.org/10.1097/01.tp.0000131163.43015.85 DB - PRIME DP - Unbound Medicine ER -