Bag-1 up-regulation in anti-CD4 mAb-treated allo-activated T cell confers resistance to activation-induced cell death (AICD).
The non-depleting anti-CD4 monoclonal antibody (mAb) RIB5/2 is a powerful inducer of tolerance to major histocompatibility complex (MHC)-incompatible allografts in rat recipients. The unresponsiveness induced is characterized by the persistence (over 300 days) of donor-reactive regulatory T cells within the graft. We applied differential-display reverse-transcription polymerase chain reaction (RT-PCR) to identify differences at the mRNA level between graft-infiltrating cells of anti-CD4 mAb-treated and non-treated control rats at day 5 after kidney transplantation. A 550-bp DNA fragment appearing only in anti-CD4 mAb-treated rats is identical with the anti-apoptotic protein Bag-1. A further investigation of Bag-1 expression during mixed lymphocyte reactions (MLR) revealed a three-four-fold up-regulation of Bag-1 mRNA expression in anti-CD4 mAb-treated allogeneic cultures. Bag-1 up-regulation is associated with higher protection against apoptosis of anti-CD4 mAb-treated cultures. Application of antisense oligonucleotides specific for Bag-1 leads to both a reduction in Bag-1 expression and sensibility against apoptosis. Thus, the expression of Bag-1 in anti-CD4 mAb-treated alloreactive T cells conferred resistance against apoptosis, which may contribute to the long-term survival of tolerance-mediating T cells in vivo.
Department of Medical Immunology, Humboldt-University Berlin, Germany.
Birgit
B
Sawitzki
Manfred
M
Lehmann
Katrin
K
Vogt
Martina
M
Seifert
Kirsten
K
Risch
Josef
J
Brock
Jerzy W
JW
Kupiec-Weglinski
Hans-Dieter
HD
Volk
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000502:physiology; D017209:Apoptosis; D015704:CD4 Antigens / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D020869:Gene Expression Profiling; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000911:Antibodies, Monoclonal; C091732:BCL2-associated athanogene 1 protein; C494813:Bcl2l1 protein, rat; D015704:CD4 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007519:Isoantigens; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein