Elimination of donor-specific alloreactivity prevents cytomegalovirus-accelerated chronic rejection in rat small bowel and heart transplants.
BACKGROUND
The primary cause for late failure of vascularized allografts is chronic rejection (CR) characterized by transplant vascular sclerosis (TVS). Cytomegalovirus (CMV) infection accelerates TVS and CR by unclear mechanisms involving direct effects of CMV, indirect effects of the recipient's immune response to CMV, or interactions between CMV and the recipient's alloreactivity. This study examined the role of CMV and the alloreactive response in the development of TVS using bone marrow chimerism (BMC) in rat small bowel (SB) and heart transplantation models.


METHODS
Fisher 344 (F344) rat heart or SB grafts were transplanted into F344/Lewis bone marrow chimera. F344 heart or SB grafts transplanted into Lewis recipients (low-dose cyclosporine) were positive controls for the development of TVS. Lewis heart or SB grafts transplanted into Lewis recipients (+/-cyclosporine) were transplantation controls. The effect of rat CMV (RCMV) (5x105 plaque-forming units) on TVS (neointimal index, NI) and graft survival was studied in these groups. RCMV infection was assessed by serologic analysis and quantitative polymerase chain reaction techniques (TaqMan).


RESULTS
RCMV infection accelerated the time to graft CR (SB 70-38 days; hearts 90-45 days) and increased the severity of TVS in both the SB allografts (day 38, NI=27 vs. 52) and the heart allografts (day 45, NI=43 vs. 83). Grafts from CMV-infected syngeneic recipients failed to develop TVS and CR. Donor-specific tolerance induced by BMC prevented allograft TVS and CR in both transplant models. In contrast to naïve Lewis recipients, RMCV infection failed to cause allograft TVS and CR in bone marrow (BM) chimeras.


CONCLUSIONS
The events in CMV-induced acceleration of TVS involve a crucial interplay between CMV infection and the recipient's alloreactive immune response.
Orloff
Susan L
SL
Portland Veterans Affairs Medical Center, Portland, Oregon 97201, USA. orloffs@ohsu.edu
Streblow
Daniel N
DN
Soderberg-Naucler
Cecilia
C
Yin
Qiang
Q
Kreklywich
Craig
C
Corless
Christopher L
CL
Smith
Patricia A
PA
Loomis
Christopher B
CB
Mills
Lisa K
LK
Cook
Judith W
JW
Bruggeman
Catherine A
CA
Nelson
Jay A
JA
Wagner
Cynthia R
CR
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D002908:Chronic Disease; D003586:Cytomegalovirus Infections / Q000150:complications*; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007421:Intestine, Small / Q000637:transplantation*; D007519:Isoantigens / Q000276:immunology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012598:Sclerosis; D014019:Tissue Donors
D007519:Isoantigens