Background. Blood transfusion before organ transplantation has a beneficial effect on allograft survival; the mechanism of this effect has remained a mystery. In murine models, the presence of common histocompatibility antigens in the blood donor and the recipient favors the induction of allograft tolerance. Methods. To investigate the effect of HLA compatibility between blood donor and recipient on the induction of allograft tolerance, we determined the relative frequency of cytotoxic T-lymphocyte precursors specific for donor cells before and at several times after blood transfusion in 23 patients awaiting a first renal transplant. We correlated the results with the presence of shared HLA antigens. Results. T-cell nonresponsiveness against donor cells developed after blood transfusion in 10 of the 23 patients. Tolerance developed only if the blood donor and the recipient had one HLA haplotype or at least one HLA-B and one HLA-DR antigen in common (as was observed in 9 of these 10 patients). Tol...

Pretransplantation Blood Transfusion Revisited

Background. Although HLA typing and matching have been used for 3 decades, that practice has been poorly implemented in corneal transplantation, mainly because of inconclusive or contradictory analytical results. Consequently, we studied the immune response of corneal transplant recipients to HLA histoincompatibilities in a large homogeneous study. Methods. All corneal transplantations performed by a single surgeon between 1976 and 1996 were studied. HLA-AB matching was used for recipient selection. All HLA typings were performed by a single experienced laboratory. Population genetic techniques were used to assess the validity of the HLA typings. Mono- and multivariate analyses were performed to identify the factors which significantly influence the survival of corneal allografts. Simulation studies were carried out to demonstrate the effects of mis-typed donor and recipient HLA-DR typings on analytical results. Results. Retransplantation, degree of vascularization, HLA-AB and DR matching, endothelial cell count, graft size, recipient gender, and storage method were identified as significant factors by our monovariate analyses. A Cox proportional hazards survival analysis model identified degree of vascularization and HLA-AB and DR matching as significant prognostic factors when all immunological rejection episodes were used, P=0.000001. When only irreversible immunological rejection episodes were used, panel reactive antibodies, retransplantation, and number of rejection events were also identified, P=0.000001. Simulation studies showed that the effects of HLA-DR matching are abrogated by poor HLA-DR typings. Conclusions. Corneal allograft recipients have a normal alloimmune response to histoincompatibilities. Demonstration of that fact requires accurate HLA typings.

Beneficial effect of HLA-DR matching on the survival of corneal allografts.

Methods of inducing tolerance including administering to the recipient a short course of help reducing treatment or administering a short course and methods of prolonging the acceptance of a graft by administering a short course of an immunosuppressant.

Allogeneic and xenogeneic transplantation

Background The immune mechanisms by which corneal allografts are rejected in normal ocular graft beds have not been identified. Both acceptors and rejectors of these types of grafts display donor-specific delayed hypersensitivity and in vitro proliferating primed T cells, yet neither develop conventional, donor-specific cytotoxic T cells. We wished to determine whether unconventional donor-specific cytotoxic T cells are generated in rejector mice that recognize donor minor alloantigens presented by recipient major histocompatibility complex (MHC) molecules. Methods BALB/c mice received orthotopic corneal allografts from C57BL/10 donors in normal eyes. At 4 weeks (when 50% of grafts can be designated as rejected), primed cytotoxic T lymphocyte (CTL) activity in draining lymph nodes and spleen was assayed on targets selected to present donor-type minor H antigens on recipient MHC molecules. Control mice received heterotopic corneal allografts and were similarly examined. Results Lymphoid organs of recipients that rejected orthotopic or heterotopic corneal allografts contained CTL that lysed targets expressing donor-type minor H antigens presented by recipient MHC molecules. By contrast, no CTL activity was detected from lymphoid cells of recipients that accepted orthotopic corneal allografts. Rejection of orthotopic corneal allografts placed into normal mouse eyes correlates directly with the generation of donor-specific CTL that recognize minor H antigens in the context of recipients MHC molecules. Conclusions These results indicate the indirect pathway of alloantigen presentation is the only pathway operative in the process by which orthotopic corneal allografts are rejected. The roles of emigrant Langerhans cells and corneal lymphatics in the indirect pathway are discussed.

Detection of minor alloantigen-specific cytotoxic T cells after rejection of murine orthotopic corneal allografts: evidence that graft antigens are recognized exclusively via the "indirect pathway".

Though keratoplasty is the most successful transplantation [1], corneal graft rejection is still the most frequent complication after corneal grafting and often leads t

Corneal allograft rejection: current understanding. 2. Clinical implications.

Transplantation of unmatched allogeneic corneas into highly vascularized recipient eyes under the cover of short-term immunosuppression with cyclosporine enables permanent engraftment. The aim of this study was to further elucidate the mechanism(s) underlying this tolerant state. In eight "high-risk" cornea recipients the clone sizes of donor-specific and third-party reactive cytotoxic T cell precursors were assessed by limiting dilution analyses before and at three and six months after transplantation. Acquired allograft tolerance in these patients was not accompanied by clonal reduction of donor-specific CTL-p, whereas in the case of an irreversible rejection the donor-specific CTL pool size was significantly enlarged. This donor-specific CTL-p increase could already be seen two months before clinical manifestation. These patterns differed from that of tolerant renal transplant patients, in whom marked and donor-specific reduction of CTL-p was observed. During rejection identical patterns with increasing donor-specific CTL-p frequencies were seen in both groups of patients. We conclude that induction of tolerance by short-term CsA to unmatched cornea grafts is not caused by clonal reduction of the effector precursor cell pool.

Studies of the mechanism of tolerance induced by short-term immunosuppression with cyclosporine in high-risk corneal allograft recipients. I. Analysis of CTL precursor frequencies.

Clonal reduction of CTL-P and acquired allograft tolerance in various human transplantation models.

Interferon (IFN) bezeichnet eine Gruppe von Zytokinen mit multiplen biologischen Wirkungen [1], Das Wirkspektrum dieser Mediatormolekule umfast antivirale, antiproliferative, differenzierungsinduzierende und immunmodulierende Aktivitaten [2]. Praklinische Testungen einzelner IFN-Aktivitaten erlauben daher keine sichere Aussage uber komplexe Wirkungen in vivo. Der adaquate und gezielte Einsatz von Zytokinen zwingt deshalb zu aufwendigen praklinischen Untersuchungen und extensiver Prufung in klinischen Studien [3, 4, 5]. Ziel unserer Untersuchungen im Rahmen von onkologischen IFN- Phase-I/II-Studien war einerseits die Entwicklung pradiktiver Tests zur Selektion IFN-α-sensibler CML-Patienten, andererseits die Etablierung einer neuen Strategie zum optimalen Einsatz von IFN-γ in der Therapie des metastasierenden Hypernephroms.

Präklinische Testung und Verlaufsparameter bei Interferon-Therapie

Recently interferon- γ (IFN- γ) has been widely tested in clinical trials. These studies investigated not only efficacy but also several immunomodulatory properties of the cytokine [1–4]. In all studies published so far, IFN-γ was administered three to seven times weekly. The effects of single doses of IFN- γ have not been investigated in detail. The present study aimed at testing the effect that different dose levels of IFN- γ administered as a single dose have on white blood cell counts, number of T cell subsets, natural killer (NK) cells and human leukocyte antigen (Major histocompahibility antigens class II) (HLA) DR positive cells in the peripheral blood of patients treated for metastasizing renal cell cancer.

Acute Effects of Recombinant IFN-γ on White Blood Cell Counts and Lymphocyte Subsets in the Peripheral Blood of Cancer Patients

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Studies of the mechanism of tolerance induced by short-term immunosuppression with cyclosporine in high-risk corneal allograft recipients. I. Analysis of CTL precursor frequencies.

Clonal reduction of CTL-P and acquired allograft tolerance in various human transplantation models.

Präklinische Testung und Verlaufsparameter bei Interferon-Therapie

Acute Effects of Recombinant IFN-γ on White Blood Cell Counts and Lymphocyte Subsets in the Peripheral Blood of Cancer Patients