Mechanisms of induction of renal allograft tolerance in CD45RB-treated mice.
BACKGROUND
Rejection is the most significant problem in the field of transplantation. The current goal of transplant immunology is to develop better immunotherapeutic protocols that are aimed at specifically suppressing alloreactivity and preserving an otherwise intact immune system. We have previously shown that mice will accept renal allografts indefinitely with normal renal function after two injections of a monoclonal antibody to the CD45RB protein. Furthermore, this antibody will reverse acute rejection when therapy is delayed until day 4 and will still induce tolerance. The mechanisms of this therapeutic benefit are not known.


METHODS
BALB/C mice were used as recipients of major multiple histocompatibility complex-mismatched kidneys using C57BL/6 as donors. Immunoperoxidase microscopy and Northern blots for cytokine gene expression were used to study the renal allografts. Fluorescence-activated cell sorter (FACS) analyses of peripheral blood lymphocytes were performed. Phosphotyrosine peptide phosphatase assays were performed on splenic lymphocyte membranes.


RESULTS
A CD45RB monoclonal antibody (MB23G2) induced tolerance and partially depletes peripheral blood lymphocytes. A therapeutically ineffective CD45RB monoclonal antibody (MB4B4) merely coated the circulating lymphocytes. Furthermore, MB23G2 stimulated more tyrosine phosphatase activity than MB4B4 in mouse T-cell membranes.


CONCLUSIONS
The clearance of peripheral blood lymphocyte populations and stimulation of protein tyrosine phosphatase activity may be important in the mechanism of tolerance induction by CD45RB therapy, which may be clinically relevant in the therapy of organ rejection in humans.
Lazarovits
A I
AI
John P. Robarts Research Institute, London Health Sciences Centre, Ontario, Canada. alazarov@julian.uwo.ca
Visser
L
L
Asfar
S
S
LeFeuvre-Haddad
C E
CE
Zhong
T
T
Kelvin
D J
DJ
Kong
C
C
Khandaker
M H
MH
Singh
B
B
White
M
M
Jevnikar
A M
AM
Zhang
Z
Z
Poppema
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases