Pi. Hornick et al., ASSESSMENT OF THE CONTRIBUTION THAT DIRECT ALLORECOGNITION MAKES TO THE PROGRESSION OF CHRONIC CARDIAC TRANSPLANT REJECTION IN HUMANS, Circulation, 97(13), 1998, pp. 1257-1263
Citations number
55
Categorie Soggetti
Peripheal Vascular Diseas",Hematology,"Cardiac & Cardiovascular System
Background-Two populations of T cells contribute to allograft rejectio
n. T cells with direct allospecificity are activated after recognition
of intact MHC alloantigens displayed at the surface of donor passenge
r leukocytes carried within the graft. In contrast, T cells with indir
ect allospecificity recognize donor alloantigens as processed peptides
associated with self (recipient)-MHC class II molecules. In small ani
mal models of transplantation, direct pathway T cells dominate the acu
te rejection process and are rendered tolerant to the graft after the
loss of donor passenger leukocytes. It has been argued that indirect p
athway T cells contribute substantially to continual graft damage afte
r passenger cell loss. The purpose of this study was to determine whet
her donor-specific tolerance could be detected in T cells with direct
anti-donor allospecificity in human heart transplant recipients after
prolonged graft residence.Methods and Results-Alloreactive helper (HTL
f) and cytotoxic (CTLf) T cells were enumerated by use of limiting dil
ution analysis, These assay systems were refined to make them specific
for the direct pathway of allorecognition and more sensitive in the c
ase of the HTLf assay, Recipient:anti-donor frequencies were generated
in 10 long-term recipients of heart grafts with progressive chronic r
ejection and compared with those against equivalently HLA mismatched r
ecipient:third-party controls. For HTLf, direct pathway donor-specific
hyporesponsiveness was detected in 5 of the 10 recipients (HTLf <1:10
0 000), Of these 5 recipients, 4 also had low anti-donor CTLf (<1:100
000), In the 5th recipient, although the CTLf was >1:100 000, it was s
ignificantly lower than that estimated against the third-party control
. Conclusions-Donor-specific hyporesponsiveness is demonstrated in 50%
of recipients in both the HTLf and CTLf compartments of the direct al
loresponse. Direct allorecognition therefore appears unlikely to be re
sponsible for the progression of chronic rejection, implicating indire
ct allorecognition as the predominant immunological driving force. Fur
thermore, these data have potential implications for graft outcome, ad
justment of immunosuppression, and recipient monitoring.