From the Departments of Immunology (P.I.H., P.D.M., R.B., R.I.L.) and
Cardiothoracic Surgery (P.I.H.), Royal Postgraduate Medical School,
Hammersmith Hospital, London, UK, and the Department of Cardiothoracic
Surgery, Harefield Hospital (M.H.Y., M.L.R.), Middlesex, UK.
Correspondence to Philip Hornick, Department of Cardiothoracic Surgery, Royal Postgraduate Medical School, DuCane Rd, Hammersmith Hospital, London W12 ONN, UK.
Background—Two populations of T
cells contribute to allograft rejection. T cells with direct
allospecificity are activated after recognition of intact MHC
alloantigens displayed at the surface of donor passenger leukocytes
carried within the graft. In contrast, T cells with indirect
allospecificity recognize donor alloantigens as processed peptides
associated with self (recipient)–MHC class II molecules. In small
animal models of transplantation, direct pathway T cells dominate the
acute rejection process and are rendered tolerant to the graft after
the loss of donor passenger leukocytes. It has been argued that
indirect pathway T cells contribute substantially to continual graft
damage after passenger cell loss. The purpose of this study was to
determine whether 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 (HTLf) and cytotoxic
(CTLf) T cells were enumerated by use of limiting dilution
analysis. These assay systems were refined to make them
specific for the direct pathway of allorecognition and more sensitive
in the case of the HTLf assay. Recipient:anti-donor frequencies were
generated in 10 long-term recipients of heart grafts with progressive
chronic rejection and compared with those against equivalently HLA
mismatched recipient:third-party controls. For HTLf, direct pathway
donor-specific hyporesponsiveness was detected in 5 of the 10
recipients (HTLf <1:100 000). 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 significantly 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
alloresponse. Direct allorecognition therefore appears unlikely to be
responsible for the progression of chronic rejection, implicating
indirect allorecognition as the predominant immunological driving
force. Furthermore, these data have potential implications for graft
outcome, adjustment of immunosuppression, and recipient monitoring.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Assessment of the Contribution That Direct Allorecognition Makes to the Progression of Chronic Cardiac Transplant Rejection in Humans
Key Words: transplantation • immunology • rejection • immune system • lymphocytes
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