Class I loci were typed at low, class II at high resolution, all using molecular methods. == Penetrating keratoplasty and medical aftercare == All grafts were kept in organ culture for at least 6 days. those thresholds in the second cohort. We applied Cox proportional hazards regression for these analyses. == Results == The thresholds with highest predictive power revealed 220 eplets2for the tolerance factor and 10 eplets for HLA-class I histocompatibility. The respective hazards ratios were 2.22 (p=0.04) versus 3.63 (p<0.01) in the first cohort and 2.09 (p<0.01) versus 1.51 (p=0.02) in the second, confirmatory cohort. The threshold factors proved to be additive in predicting immune reactions in both cohorts, (hazard ratios 2.66 in cohort 1 versus 1.70; p<0.01 in cohort 2). == Conclusions == Operational tolerance may be inducible by balanced matching of HLA-class I and II HLAMatchmaker eplets. Furthermore, such tolerance is usually additive to histocompatibliity at HLA-class I. == Introduction == Corneal diseases are among the five most common causes of blindness. Penetrating keratoplasty can restore vision in most cases. Yet a substantial percentage of grafts fail following immunologic rejection. Cumulative graft survival after five years is as low as 70% for all those keratoplasty indications despite the widespread use of topical steroids [1]. Systemic immunoprophylaxis can improve overall graft survival in keratoplasty [2,3]. However, most ophthalmologists are reluctant to prescribe long-term systemic immunosuppressants because of potentially serious side effects. This circumstance reinforces our need for effective main prophylaxis of immunologic graft reactions. Graft rejection can be prevented employing graft-masquerade by human leukocyte antigen (HLA) matching, according to a recent statement [4]. The controversial older literature in this field is usually biased due to low statistical power (too small cohorts) as well as the probably low accuracy of the HLA typings at that time [5]. HLA matching is usually, however, associated with prolonged waiting times depending on the individual Tulobuterol HLA phenotype [6]. HLA matching is usually thus only routine nowadays in highly specialized transplantation centers. Allo-specific tolerance is usually a related but unique mechanism of long-term graft survival after withdrawal Tulobuterol of all immunosuppressants. Graft rejection is usually prevented by alloantigen-specific immune regulation [7]. Consequently, donor-specific suppression of delayed-type hypersensitivity has been demonstrated in some long-term graft acceptors after kidney transplantation [8]. At least one major histocompatibility complex (MHC) locus must match between donor and recipient to induce allo-specific tolerance in the miniature swine model of kidney transplantation [9]. Good histocompatibility at the swine leukocyte antigen (SLA)-class II loci were considered inducive to tolerance in this large animal model, even when class I loci were loosely matched [10]. These findings resemble clinical observations in long-time survivors Rabbit Polyclonal to Tubulin beta after kidney transplantation [8,11]. Additionally, the beneficial pre-blood transfusion effect is also ascribed to a loosely-matched HLA-class I loci in conjunction with closer agreement at HLA-class II [12]. On that basis, we hypothesized that matching at the HLA-DR locus more closely than at loci HLA-A and -B would induce graft tolerance in keratoplasty. However, conventional HLA-allele-based matching might be improper for detecting Tulobuterol this effect in the rather small HLA-typed cohorts available after keratoplasty. Moreover, the standard matching approach would not reflect structural or functional similarities between HLA alleles. HLAMatchmaker, by contrast, quantitatively assesses donor-recipient histocompatibility on the basis of polymorphic amino acid configurations (eplets) that represent structurally defined elements of the HLA epitopes [13]. HLAMatchmaker has already proved effective for quantitatively assessing HLA-class I histocompatibility in penetrating keratoplasty [14], and has recently been expanded to accommodate HLA-class II [15]. This new version enables us to test Tulobuterol for the first time whether tolerance is usually induced from balanced histocompatibility at HLA-DR (class II) versus HLA-A and -B Tulobuterol (class I). == Methods == == Patients == We selected two impartial cohorts of penetrating keratoplasties (Table 1). Complete HLA-A, -B, and -DR types were available for all donors and recipients in both groups. == Table 1. Two examples for calculating the tolerogenicity factor from your donors and recipients HLA-phenotypes. == Mismatched donor alleles are in boldface. The count of eplet mismatches was determined by HLAMachmaker. Eplet mismatches for HLA-A/B function as factor.