Bortezomib and sirolimus inhibit the chronic active antibody-mediated rejection in experimental renal transplantation in the rat.
BACKGROUND
To date, no effective immunosuppressive standard for the prevention or treatment of alloantibody production in acute and chronic rejection of renal transplants has been established. Alloantibody formation has been recognized in the well-established rat model of Fischer to Lewis renal transplantation. We used this renal allotransplantation model to test the effectiveness of sirolimus (SRL), bortezomib (BZ) or their combination in an already established humoral rejection situation.


METHODS
After 3 weeks, transplanted rats were treated either with placebo (P), SRL, BZ or combination of SRL and BZ. Rats were monitored for donor-specific alloantibodies as well as humoral responses in the spleen and bone marrow, renal function and histological changes in the graft.


RESULTS
In all three treatment arms, glomerular, tubulointerstitial and vascular changes of chronic antibody-mediated rejection were ameliorated compared to the P group. Production of alloantibodies against components of glomerular basement membrane was reduced in all three treatment arms. The humoral response was strongly reduced, as shown by decreased numbers of IgG-secreting cells, plasma cells and partially B cells in all treatment groups with a trend of SRL/BZ combination being most effective. Infiltration of the graft with inflammatory cells like cytotoxic T cells, T helper cells, B cells and macrophages was efficiently blocked by BZ and the SRL/BZ combination and, except for B cells, by SRL.


CONCLUSIONS
BZ and SRL represent promising drugs with anti-humoral activity in the situation of an already established chronic humoral or mixed alloimmune response after renal transplantation.
Vogelbacher
Regina
R
Medical Clinic IV (Nephrology), University of Erlangen-Nürnberg, Germany.
Meister
Silke
S
Gückel
Eva
E
Starke
Charlotte
C
Wittmann
Sandra
S
Stief
Andrea
A
Voll
Reinhard
R
Daniel
Christoph
C
Hugo
Christian
C
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002908:Chronic Disease; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008212:Lymphocyte Depletion; D008297:Male; D010950:Plasma Cells / Q000502:physiology; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D001897:Boronic Acids; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011719:Pyrazines; D000069286:Bortezomib; D020123:Sirolimus