Circulating donor-specific cytotoxic T lymphocytes with high avidity for donor human leukocyte antigens in pediatric and adult cardiac allograft valved conduit recipients✩

Abstract

Objective: Speci®c immunological responses may be involved in the process of cryopreserved allograft valved conduit (AVC) degeneration, which is more frequently seen in young recipients. Rejection of heart and corneal allografts is preceded by an increase in the fraction of cytotoxic T lymphocytes (CTL) with high avidity for donor human leukocyte antigens (HLA) circulating in both peripheral blood and the affected graft. These donor-speci®c high-avidity CTLs are regarded as the destructive cells capable of causing graft damage. To monitor the precursors of these cells (CTLp) in young and adult AVC recipients, in vitro quantitative tests were performed on sequentially taken blood samples to quantitate CTLp frequencies and their avidity for donor antigens. Method: Six children and nine adults who received a cryopreserved AVC in the period between 1994 and 1997 were included in the study. From these patients, two to six blood samples were obtained up to 3 years after valve implantation. The number of circulating CTLp present within the peripheral blood mononuclear cell (PBMC) population was determined by limiting dilution analysis (LDA). The fraction of CTLp with high avidity for donor HLA class I was determined by addition of CD8 monoclonal antibodies (mAb) during the cytotoxic phase of the assay. Third-party stimulator cells were used to verify the donor-speci®city of the response. Results: The number of donor-speci®c CTLp increased signi®cantly in the period 6±12 months after AVC implantation, while third-party-speci®c CTLp frequencies were not affected. Additionally, we found a signi®cant increase of the high-avidity fraction of CTLp directed against donor antigens as early as during the ®rst 6 months after AVC implantation. The fraction of high-avidity CTLp remained signi®cantly higher post-compared with pre-implantation, even after 12 months. We observed no signi®cant difference in the kinetics of CTLp frequencies between pediatric and adult AVC recipients. Conclusion: Implantation of cryopreserved human AVC induces an increase in the total number of circulating CTLp directed against donor HLA class I in both adults and children. The shift towards more destructive high-avidity CTLp in the peripheral blood indicates their potential damaging effect towards the heart valve allograft. q

Mechanical Compliance and Immunological Compatibility of Fixative-Free Decellularized/Cryopreserved Human Pericardium

“…Although we did not specifically investigate the subclasses of CD8 + circulating cells, this observation appears particularly relevant in the view of homograft transplantation of the DE/CR tissue. In fact, GA-fixed pericardial implants are known to cause an increase of circulating cytotoxic [18] or helper [19] T cells and production of anti HLA-I antibodies, which correlate with graft failure [17]. Thus, the fixative-free decellularization/cryopreservation method used in the present study may be helpful to reduce the inflammatory and cell-mediated immune response in recipients, improving the long-term durability of the implants.…”

“…We and others have found that patients receiving allograft valve transplantation show increased serum levels of anti HLA-1 antibodies [17] and of circulating cytotoxic and helper T-lymphocytes (CTLs, HTLs) [18], [19].…”

Use of an allograft patch in repair of hypoplastic left heart syndrome may complicate future transplantation

“…Studies have also correlated HLA mismatch with increased rate of allograft valve failure [11,12]. Other studies in humans and animals have demonstrated an increase in donor-specific cytotoxic [13] and helper Tlymphocyte precursors [3]. Using a rat model our group [4] and others [5] have also demonstrated an early and intense cytotoxic T-lymphocyte response along with complete destruction of valve leaflets in allogeneic rats.…”

Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation

“…Monitoring of donor-reactive immune responses has demonstrated that hyporesponsiveness to the direct pathway can develop shortly after solid organ transplantation and is in general associated with stable graft function (Hornick et al, 1998; De Haan et al, 2000). Donor-specific cytotoxic or T cell hyporesponsiveness has been detected in kidney (Ghobrial et al, 1994; Mason et al, 1996; Mestre et al, 1996; Hornick et al, 1998; Baker et al, 2001b), heart (Hu et al, 1994; Hornick et al, 2000; Van Hoffen et al, 2000) and lung (De Haan et al, 2000) transplantation, although this is not a universal finding (Eberspacher et al, 1994; Loonen et al, 1994; Steinmann et al, 1994; Oei et al, 2000). In addition, hyporesponsivessness to donor antigen presented by the indirect pathway has also been described (Salama et al, 2003b).…”