Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.
BACKGROUND
We hypothesized that T-regulatory cells specific for donor alloantigens would protect a renal transplant during partial withdrawal of immunosuppression.


METHODS
To test this hypothesis, 32 renal transplant recipients aged 55 years and older with excellent renal function were tested for donor-specific regulation (DSR) by trans-vivo delayed type hypersensitivity assay at the time of enrollment (T=0) and 6 months later (T=6). Twenty-two patients had prednisone withdrawn during a 3-month period, whereas 10 controls were maintained on triple therapy (prednisone, cyclosporine, and mycophenolate).


RESULTS
Of 22 patients in the steroid withdrawal group, 10 were DSR+ and 12 were DSR- at the time of enrollment (T=0). None of the DSR+ patients experienced acute rejection, nor did any have donor-specific human leukocyte antigen (HLA) antibody during or after withdrawal. Of 12 DSR- patients, three developed acute rejection, which were reversed with bolus steroid treatment, and four were donor-specific antibody+ at T=0 or T=6. Two years later, 80% (8 of 10) of DSR+ patients in the withdrawal group remain steroid free while maintaining excellent renal function, as compared with only 58% (7 of 12) DSR- patients. Patient survival at 4 years was similar for DSR+ (9 of 10) and DSR- (11 of 12) patients in the withdrawal group. Patients maintained on triple therapy remained rejection free during the 4-year follow-up regardless of initial DSR status, with patient survival rate of 70% (7 of 10).


CONCLUSIONS
DSR before steroid withdrawal may identify a subset of transplant patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.
Jankowska-Gan
Ewa
E
Department of Surgery, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
Sollinger
Hans W
HW
Pirsch
John D
JD
Cai
Junchao
J
Pascual
Julio
J
Haynes
Lynn D
LD
Munoz del Rio
Alenjandro
A
Burlingham
William J
WJ
D000208:Acute Disease; D000368:Aged; D000375:Aging / Q000276:immunology*; D000818:Animals; D065095:Calcineurin Inhibitors; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D006968:Hypersensitivity, Delayed; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011241:Prednisone / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014019:Tissue Donors
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D011241:Prednisone
J Clin Invest. 1998 Jan 15;101(2):398-405
9435312
Am J Transplant. 2004 Apr;4(4):537-43
15023145
Transplantation. 2007 Aug 15;84(3):392-9
17700166
Transplantation. 1994 Feb;57(3):446-50
8108881
Transplantation. 1992 Jan;53(1):55-9
1733086
Am J Transplant. 2008 Feb;8(2):307-16
18211506
Am J Transplant. 2007 Feb;7(2):466-70
17173656
Blood. 2005 Dec 1;106(12):3860-6
16118322
J Immunol. 2007 Mar 15;178(6):3983-95
17339499
J Clin Invest. 2000 Jul;106(1):145-55
10880058
Transplantation. 1982 May;33(5):515-7
7046163
Hum Immunol. 2000 Dec;61(12):1395-402
11163098
Curr Opin Nephrol Hypertens. 2007 Nov;16(6):535-41
18089967
Hum Immunol. 1999 Aug;60(8):640-51
10439310
J Immunol. 2007 Nov 15;179(10):6749-61
17982065
Am J Kidney Dis. 1994 Jan;23(1):1-15
8285183
Transplantation. 1998 Apr 27;65(8):1115-23
9583874
J Clin Invest. 2007 Nov;117(11):3498-506
17965778
Am J Respir Crit Care Med. 2008 Mar 15;177(6):660-8
18174545
Clin Transplant. 1994 Jun;8(3 Pt 2):332-5
8061376
Blood. 2003 Sep 15;102(6):2180-6
12775574
J Clin Invest. 2004 Dec;114(11):1640-9
15578096
Am J Transplant. 2002 Nov;2(10):926-33
12482144
J Immunol. 2001 Nov 15;167(10):5522-6
11698419
Hum Immunol. 2007 Jun;68(6):514-22
17509451
N Engl J Med. 2003 Dec 11;349(24):2326-33
14668458
Am J Kidney Dis. 1999 May;33(5):829-39
10213637
Transplant Proc. 2000 Feb;32(1A Suppl):6S-8S
10686310
J Immunol. 2004 May 1;172(9):5753-64
15100322
J Immunol. 2000 Feb 15;164(4):2240-7
10657680
Am J Transplant. 2009 May;9(5):1087-98
19344431
J Exp Med. 2004 Apr 5;199(7):1017-23
15067036
Immunol Today. 1999 Feb;20(2):77-82
10098326
Transplantation. 2001 Aug 27;72(4):571-80
11544414
J Am Soc Nephrol. 2004 Jul;15(7):1952-60
15213286
J Immunol. 2007 Sep 15;179(6):3443-51
17785778
Nat Med. 2005 Jun;11(6):605-13
15937473
Transplantation. 1999 Dec 27;68(12):1865-74
10628766
Prog Clin Biol Res. 1986;224:87-117
2948196
Transplant Proc. 1998 Dec;30(8):4294-6
9865366
Hum Immunol. 2002 Oct;63(10):862-70
12368038