Induction of specific tolerance through mixed hematopoietic chimerism prevents chronic renal allograft rejection in a rat model.
BACKGROUND
Chronic rejection is the leading cause of late graft loss in kidney transplantation. We tested the ability of mixed hematopoietic chimerism to prevent chronic renal allograft rejection in an established rat model and described possible mechanisms responsible for this tolerance.


METHODS
Mixed hematopoietic chimerism was established in lethally irradiated F-344 rats by reconstitution with Lewis bone marrow. Four groups (n = 5 each) received orthotopic kidney transplants: (1) allograft controls, (2) isograft controls, (3) experimental chimeras, and (4) specificity control. After 120 days kidney grafts were examined histologically, immunohistochemically, and for cytokine interferon-gamma, interleukin-2 (IL-2), IL-4, and IL-10 gene transcripts by means of reverse transcriptase polymerase chain reaction techniques.


RESULTS
Allograft control group exhibited severe parenchymal fibrosis; isograft control and chimera groups failed to develop this lesion. Immunohistochemical analysis revealed increased CD8+ lymphocytes and ED-1+ monocyte-macrophages infiltrating the tubulointerstitium of control allografts. Interferon-gamma and IL-2 were absent in isografts. IL-4 was absent and IL-10 was positive in all grafts. Chimeras promptly rejected third-party allografts.


CONCLUSIONS
Induction of specific tolerance through mixed hematopoietic chimerism prevents chronic renal allograft rejection. These results support the hypothesis of an immunologic basis of chronic rejection and advance previous observations that the induction of specific tolerance enables long-term solid organ transplantation without the use of immunosuppression.
Blom
D
D
Department of Surgery, University of Rochester School of Medicine and Dentistry, N.Y, USA.
Morrissey
N J
NJ
Mesonero
C
C
Coppage
M
M
Fisher
T
T
Zuo
X J
XJ
Jordan
S C
SC
Orloff
M S
MS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002678:Chimera; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection / Q000517:prevention & control*; D006410:Hematopoiesis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D016030:Kidney Transplantation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018655:Lymphocyte Count; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D016207:Cytokines; D012333:RNA, Messenger