Lymphoid/nonlymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct bone marrow.
BACKGROUND
The role of leukocyte migration and chimerism in organ allograft acceptance has been obscured by the lack of information about the late localization of the donor cells.


METHODS
Male Lewis rat-->female Brown Norway abdominal heart transplantation was performed under tacrolimus immunosuppression (days 0-13, 20, and 27) with or without donor bone marrow and (in bone marrow subgroups) a 1-week postoperative course of a possibly chimerism-enhancing drug. Using rat sex-determining region-Y-specific oligonucleotide primers, we determined the donor DNA concentration by polymerase chain reaction in serial venous blood samples for 100 days and in tissue specimens when animals were killed.


RESULTS
Chimerism was detected out to 56 days in 89% of the blood samples but in none of the samples at 100 days. However, donor DNA was detected when animals were killed in 95% of the native hearts, 80% of the skin biopsy specimens, and 23% of the spleens. The presence and quantity of early and late chimerism were strongly correlated the administration of adjunct bone marrow and with a reduction in the vasculopathy and inflammation index in the cardiac allografts. Marginally significant further increases in chimerism and/or reductions in chronic heart rejection beyond those achieved with adjunct bone marrow alone were associated with additional treatment with the growth factors Flt-3 ligand, granulocyte colony-stimulating factor, and a recombinant molecular variant of interleukin-6 (interleukin-6 mutein) but not with hepatocyte growth factor or lisofylline.


CONCLUSIONS
The previously suspected shift of early chimerism in the blood and lymphoid organs to dominance in host nonlymphoid tissues is consistent with the dual mechanisms of clonal exhaustion and immune indifference, governed by antigen migration and localization, that have been postulated elsewhere to account for organ allograft acceptance.
Terakura
M
M
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Murase
N
N
Demetris
A J
AJ
Ye
Q
Q
Thomson
A W
AW
Starzl
T E
TE
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002464:Cell Migration Inhibition; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology; D018183:Transplantation Chimera / Q000276:immunology*
D000276:Adjuvants, Immunologic; D016298:Hematopoietic Cell Growth Factors; D007166:Immunosuppressive Agents; C025189:lisofylline; D010431:Pentoxifylline; D016559:Tacrolimus