title: Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection.
abstract: BACKGROUND
  In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'.
  
  
  METHODS
  Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation.
  
  
  RESULTS
  At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC.
  
  
  CONCLUSIONS
  These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Theruvath
authors.forename: S L
authors.initials: SL
authors.lastname: Saidman
authors.forename: S
authors.initials: S
authors.lastname: Mauiyyedi
authors.forename: F L
authors.initials: FL
authors.lastname: Delmonico
authors.forename: W W
authors.initials: WW
authors.lastname: Williams
authors.forename: N
authors.initials: N
authors.lastname: Tolkoff-Rubin
authors.forename: A B
authors.initials: AB
authors.lastname: Collins
authors.forename: R B
authors.initials: RB
authors.lastname: Colvin
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.forename: M
authors.initials: M
authors.lastname: Pascual
mesh_terms: D000328:Adult; D000906:Antibodies / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D011446:Prospective Studies; D016559:Tacrolimus / Q000627:therapeutic use*; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus