Recurrent Autoimmune Diseases Research Articles

Hopf and Generalized Hopf Bifurcations in a Recurrent Autoimmune Disease Model

This paper is concerned with bifurcation and stability in an autoimmune model, which was established to study an important phenomenon — blips arising from such models. This model has two equilibrium solutions, disease-free equilibrium and disease equilibrium. The positivity of the solutions of the model and the global stability of the disease-free equilibrium have been proved. In this paper, we particularly focus on Hopf bifurcation which occurs from the disease equilibrium. We present a detailed study on the use of center manifold theory and normal form theory, and derive the normal form associated with Hopf bifurcation, from which the approximate amplitude of the bifurcating limit cycles and their stability conditions are obtained. Particular attention is also paid to the bifurcation of multiple limit cycles arising from generalized Hopf bifurcation, which may yield bistable phenomenon involving equilibrium and oscillating motion. This result may explain some complex dynamical behavior in real biological systems. Numerical simulations are compared with the analytical predictions to show a very good agreement.

Exploiting T cell co-inhibition to delay autoimmune disease recurrence

Abstract Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic β cells. Individuals with long-term disease are at risk of developing life-threatening complications. β cell replacement is a therapy for T1D but is limited by recurrent autoreactive T cell targeted β cell death. Thus, β cells better equipped to inhibit local T cell responses may survive longer in autoimmune recipients. Programmed-death 1 (PD-1) signaling through its ligand PD-L1 inhibits T cells, and may serve as a prominent defense in T1D. Using flow cytometric analysis, in the absence of T cells in NOD.RAG−/− mice we do not detect β cell PD-L1 expression. However, with T cells, we observed an increased proportion of β cells expressing PD-L1 in female non-obese diabetic (NOD) mice which had not developed diabetes. In addition, the majority of remaining live β cells at diabetes onset in NOD mice continue to express high levels of PD-L1. These three situations suggest that islet β cells may increase PD-L1 expression as a last line of defense to limit infiltrating T cell mediated destruction. To manipulate β cell PD-L1 expression prior to transplantation, we screened a panel of diabetes-related cytokines and found that IFN-γ enhances β cell PD-L1 expression. Unfortunately, islet transplant survival was not prolonged, which we hypothesized was due to enhanced MHC class I expression, facilitating CD8+ T cell-mediated killing. We therefore de-coupled PD-L1 from enhanced MHC I expression. Using this approach, enforced β cell PD-L1 expression delays disease recurrence. These data support our hypothesis that β cells expressing T cell co-inhibitory molecules, like PD-L1, can locally inhibit autoreactive T cells which may prevent transplant destruction.

Cell Surface Engineering for Regulation of Immune Reactions in Cell Therapy.

Transplantation of the pancreatic islets of Langerhans (islets) is a promising cell therapy for treating insulin-dependent type 1 diabetes mellitus. Islet transplantation is a minimally-invasive technique involving relatively simple surgery. However, after intraportal transplantation, the transplanted islets are attacked by the recipient's immune system, because they activate a number of systems, including coagulation, complement response, inflammation, immune rejection, and recurrence of autoimmune disease. We have developed a surface modification and microencapsulation technique that protects cells and islets with biomaterials and bioactive substances, which may be useful in clinical settings. This approach employs amphiphilic polymers, which can interact with lipid bilayer membranes, without increasing cell volume. Molecules attached to these polymers can protect transplanted cells and islets from attack by the host immune system. We expect that this surface modification technique will improve graft survival in clinical islet transplantation.

Islet allograft destruction in NOD mice is independent of donor MHC expression (TRAN3P.870)

Abstract It is unclear whether autoimmune disease recurrence overlaps with allograft immunity in the autoimmune diabetic recipient of a pancreatic islet transplant. We grafted autoimmune NOD mice with either syngeneic NOD or allogeneic C57Bl/6 (B6) islets that were genetically deficient in MHC class I, MHC class II, or both MHC class I and MHC class II. NOD.RAG-/- or MHC II-deficient NOD islets were acutely destroyed, but depletion of CD8+ T cells significantly prolonged graft survival. Most NOD MHC I-deficient or MHC I/II-deficient islets survived long-term (>100 d). In contrast, B6 allografts that were MHC sufficient, or deficient in MHC class I, class II, or both were acutely rejected. Allograft rejection was CD4+ T cell dependent and CD8+ T cell independent. Of note, islet allograft rejection in non-autoimmune recipients requires donor islet MHC I or MHC II expression. Lastly, autoimmune disease recurrence was accelerated by depletion of CD25+ cells. We hypothesize that autoimmune disease recurrence is primarily a CD8+ T cell mediated response restricted by donor MHC class I molecules and is delayed by CD4+CD25+ regulatory T cells. In contrast, results suggest that CD4+ T cells play a predominant role in allograft rejection in the autoimmune recipient. We propose the lack of down-regulation of the anti-allograft response and the presence of primed autoreactive T cells synergize to produce the rapid allograft rejection observed in the autoimmune islet transplant recipient.

Analysis of islet transplant infiltrate T cells informs design of therapeutic strategies which promote long-term euglycemia (TRAN3P.871)

Abstract NOD mice, a well-characterized model of type 1 diabetes, provide a stringent model in which to test transplant tolerance-promoting therapies. We studied the failure of T cell-directed therapies in the autoimmune recipient. When we blocked T cell co-stimulation with a CD154 antibody in NOD isograft recipients transplant survival time doubled (MST 22 days), and we observed a profound decrease in ex vivo cytokine production of graft infiltrating CD4+ T cells. These results suggest that autoimmune CD8+ T cells can mediate disease recurrence with minimal help from CD4+ T cells and that CD154 antibody does not impede the reactivation of primed autoreactive CD8+ T cells. Graft survival was significantly prolonged in NOD mice grafted with syngeneic islets and the combination treatment of CD154 antibody and transient CD8+ T cell depletion (MST 58 days). In the clinically relevant model of islet allografts in NOD mice, anti-CD154 antibody treatment had less effect on graft rejection (MST 10 days), and minimal effect on ex vivo CD4+ T cell cytokine production. Unfortunately, our combination therapy demonstrated minimal allograft survival benefits (MST 12 days). Interestingly, CD4+ T cell depletion therapy yielded superior allograft survival results (MST 24 days). These results highlight clinically relevant differences in the mechanisms of autoimmune disease recurrence and islet allograft rejection by the autoimmune recipient.

Update On Phase 2 Clinical Trial To Induce Tolerance In Mismatched Living Donor Renal Transplant Recipients

Nineteen subjects have been enrolled in a phase 2 protocol (FDA IDE 13947) to induce donor-specific tolerance in HLA-mismatched related and unrelated recipients of living donor renal allografts (KTx). The protocol is based upon tolerogenic CD8+/TCR- facilitating cells (FC) and nonmyeloablative conditioning. Recipients are conditioned with fludarabine (30 mg/kg/dose, days -5, -4, -3), cyclophosphamide (50 mg/kg/dose, day -3 and +3), 200 cGy TBI (day -1) followed by KTx (day 0). A G-CSF mobilized peripheral blood mononuclear cell product is apheresed from the donor > 2 weeks prior to the KTx, processed to remove GVHD-producing cells yet retain CD34+ cells and FC (FCRx), and cryopreserved until infusion on day +1 post-KTx. Subjects ranged in age from 18 to 65 years. All were HLA-disparate from their donors, ranging from 5 of 6 matched related to 0 of 6 unrelated. 18 of 19 subjects exhibited engraftment at 1 month; one highly sensitized subject (PRA > 50%) did not engraft. Subjects were discharged on post-operative day 2 and managed as outpatients. Mycophenolate mofetil and tacrolimus-based immunosuppression were administered for 6 months. At 6 months the MMF was discontinued if the protocol biopsy was normal and stable renal function present. Tacrolimus was weaned at month 9 (trough levels 3-6) and discontinued at 1 year if chimerism, normal renal function, and normal kidney biopsy were noted. No subjects have experienced GVHD or engraftment syndrome. Two early subjects who received a suboptimal cell dose and one other highly sensitized subject were only transiently chimeric (< 6 months); all transiently chimeric subjects resumed endogenous hematopoiesis and are maintained on low-dose tacrolimus monotherapy with stable renal function. The protocol was subsequently modified to exclude subjects with a PRA > 20%. One chimeric subject developed viral sepsis at month 3, thrombosed his kidney, and was successfully re-transplanted off study. A second subject developed CNI-induced hemolytic uremic syndrome (HUS) which resulted in graft loss. He is currently off all immunosuppression and his HUS has resolved. The remaining subjects are either off all immunosuppression (n = 9; 1 to 36 months) or are in the process of tapering. None of the chimeric subjects have developed rejection on protocol biopsy while 3 of the 5 who were not durably chimeric had Banff 1A rejection on protocol biopsy. Recurrence of autoimmune disease has occurred in 2 of 4 non-chimeric subjects, but not in any of the durable chimeric subjects. In summary, high levels of durable chimerism and tolerance without GVHD have been achieved in mismatched related and unrelated recipients of living KTx. Disclosures: Tollerud: Regenerex, LLC: Equity Ownership. Ildstad:Regenerex, LLC: Equity Ownership.

Recurrence of autoimmune liver diseases after liver transplantation: clinical aspects.

Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are autoimmune liver diseases characterized by progressive immune-mediated inflammation leading to the destruction of the hepatocytes and the biliary epithelial cells, and eventually to cirrhosis and liver failure. The ultimate treatment of these diseases, upon the establishment of end-stage liver disease, includes liver transplantation (LT). Recurrence of autoimmune liver diseases after LT is an entity increasingly recognized in the last few decades. The mechanisms driving recurrence remain poorly understood. The accurate diagnosis of the recurrence and the proper management of the affected patients remains a clinical challenge. This review discusses clinical aspects related to the recurrence of autoimmune liver diseases after LT. The main goals of this review are to discuss the reasons explaining the variability of the incidence rates of recurrent autoimmune disease and the outcome and risk factors for recurrent disease. We discuss in detail the diagnostic criteria and the treatment options of these disorders.

Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation

1. Recurrence of primary sclerosing cholangitis. a Five percent of liver transplants are performed because of end-stage liver disease secondary to primary sclerosing cholangitis. b Recurrent disease affects 10% to 27% of recipients. c Diagnostic criteria of recurrence include the following: A confirmed diagnosis of primary sclerosing cholangitis before liver transplantation. A cholangiogram showing nonanastomotic biliary strictures with beading and irregularity occurring 90 days after transplantation. Liver biopsy revealing fibrous cholangitis and/or fibro-obliterative lesions of large bile ducts. d The data argue for an association between recurrent primary sclerosing cholangitis and rejection and steroid therapy. 2. Recurrence of primary biliary cirrhosis. a Overall recurrence rates can reach 50%. b The gold standard for diagnosis is histological, with bile duct destruction by granulomas indicated by a florid lesion. c Anti-mitochondrial antibody is not a reliable marker of recurrence. d Recurrence does not affect long-term patient or graft survival. 3. Recurrence of autoimmune hepatitis. a Recurrence affects approximately 25% of liver allografts during the first 5 years after liver transplantation and more than 50% after 10 years of follow-up. b Diagnostic criteria of recurrence must include a combination of biochemical changes, (elevated serum aminotransferases levels and hypergammaglobulinemia), histological features of autoimmune hepatitis, and steroid dependency. c Immunosuppressive therapy should be pursued even if liver test results are normal.

The use of stem cells for the treatment of autoimmune diseases

Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn's disease, autoimmune blood cytopenias, and type I diabetes mellitus.

Histological recurrence of autoimmune liver diseases after living‐donor liver transplantation

The effects of living donor liver transplantation (LDLT) on the recurrence of autoimmune liver diseases have not been well documented. Genetic similarities may be beneficial to avoid severe rejection but may facilitate the recurrence of autoimmune diseases. Because familial occurrence of autoimmune liver diseases has been documented, there is a possibility that candidates for living-related donors may have the same disease as that of the recipients. Between November 1994 and June 2004, 50 patients with primary biliary cirrhosis (PBC) (16-non-blood-relative donors and 34 blood-relative donors), and 28 patients with primary sclerosing cholangitis (PSC) underwent LDLT in Kyoto University Hospital. Among 35 patients with PBC who survived more than 1 year, 10 patients (29%) showed recurrent PBC, and nine of 10 patients with recurrent PBC (90%) were associated with blood-relative donors (mean follow-up period, 30 months; range, 2-68). Two recipients had donors with some clinical or histological characteristics of PBC, and their grafts developedrecurrent PBC. Cirrhosis or graft failure was not observed in any patients with recurrent PBC. For PSC patients who survived more than 1 year after LDLT, 13 of 22 (59%) showed PSC-compatible histology and radiological findings (mean follow-up period, 31 months; range, 22-71), and five died or underwent retransplantation. Human leukocyte antigen-DR15 was positively associated with susceptibility to PSC with ulcerative colitis. One donor was revealed to have retroperitoneal fibrosis without evidence of sclerosing cholangitis. Blood-relative donors may be associated with susceptibility to recurrent autoimmune diseases. Recurrence of PSC, but not PBC, adversely affected the outcome of LDLT. Caution should be taken as blood-relative donors can be at risk of autoimmune liver diseases.

Inhalation of glutamic acid decarboxylase 65-derived peptides can protect against recurrent autoimmune but not alloimmune responses in the non-obese diabetic mouse

Systemic administration of islet-derived antigens has been shown to protect against diabetes in the non-obese diabetic (NOD) mouse by the induction of antigen-specific regulatory T cells. Bystander regulation to related and unrelated islet-derived antigens (intramolecular and intermolecular recognition) in this context is recognized. We tested if intranasal administration of glutamic acid decarboxylase 65 (GAD 65)-derived peptides could protect against both autoimmune and, through bystander regulation, alloimmune responses in a NOD mouse model. Spontaneously diabetic female NOD mice underwent islet transplantation from either C57Bl/6 or NOD islet donors. Islet recipients were treated with intranasal GAD 65-derived peptides or control (ovalbumin) peptide pre- and post-transplantation. In-vitro analysis of the effect of inhalation was defined using lymph node proliferation assays and supernatant analysis for cytokines. GAD 65-derived peptide inhalation resulted in significant protection against recurrent autoimmune disease, with the generation of an interleukin (IL)-10-producing immune phenotype in a syngeneic islet transplant model. This phenotype, however, was not robust enough to protect against alloimmune responses. Inhalation of GAD-derived peptides induces an immunoregulatory response that protects against recurrent autoimmune, but not alloimmune responses in the NOD mouse.

Pancreas transplantation using type I and type II spontaneously diabetic rats—Our experimental experience

Pancreas transplantation (PTx) is the only therapy that can cure type 1 diabetes mellitus. With the recent advance of surgical procedures and immunosuppression, the outcome of PTx has become better than it used to be before, but some problems still remain. It is rather difficult to induce tolerance and to reverse rejection once it occurred because pancreas graft itself has a strong immunogenicity. Another important issue is regarding the recurrence of autoimmune disease in the pancreatic graft, therefore, some animal models are necessary to delineate and regulate those immune responses specific for PTx. Recently, PTx is also clinically applicable for type 2 diabetic patients with end-stage renal disease. It has been shown that insulin resistance was improved by PTx in type 2 diabetic recipients. In the current study, we have introduced some useful type 1 and type 2 diabetic models mainly based on our experimental experiences.

Recurrence of Autoimmune Disease after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

There have been a number of reports on the improvement of concomitant autoimmune disease (AID) after autologous hematopoietic stem cell transplantation (SCT) performed for hematologic malignancy. However, in some cases of hematologic malignancy with AID, exacerbation of AID after autologous SCT has been reported. We have treated 27 adults with multiple myeloma with single or tandem autologous SCT. After peripheral blood stem cells were collected and stored without CD34+ cell selection or T-cell depletion, all patients received melphalan (200 mg/m2) as a conditioning regimen. In 2 patients with a history of AID (one with rheumatoid arthritis [RA] and the other with bullous pemphigoid [BP]) and in 1 patient with Sjögren syndrome, AID recurred 7 to 12 months after autologous SCT. The RA and BP were in durable remission before SCT, and no Sjögren syndrome-related disease activity was clinically documented at the time of SCT. No progression of the myeloma was observed when the AIDs recurred. The patients required systemic steroid therapy for their AID, and successful control of the disease was achieved. Our experience suggests that autologous SCT with unmanipulated stem cells for myeloma is unlikely to cure preexisting AID; rather, the AID may worsen. Transplantation physicians should be aware of this possible complication.

Identification and Functional Validation of Novel Autoantigens in Equine Uveitis

The development, progression, and recurrence of autoimmune diseases are frequently driven by a group of participatory autoantigens. We identified and characterized novel autoantigens by analyzing the autoantibody binding pattern from horses affected by spontaneous equine recurrent uveitis to the retinal proteome. Cellular retinaldehyde-binding protein (cRALBP) had not been described previously as autoantigen, but subsequent characterization in equine recurrent uveitis horses revealed B and T cell autoreactivity to this protein and established a link to epitope spreading. We further immunized healthy rats and horses with cRALBP and observed uveitis in both species with typical tissue lesions at cRALBP expression sites. The autoantibody profiling outlined here could be used in various autoimmune diseases to detect autoantigens involved in the dynamic spreading cascade or serve as predictive markers.

MHC-Mismatched Islet Allografts Are Vulnerable to Autoimmune Recognition In Vivo

When transplanted into type 1a diabetic recipients, islet allografts are subject both to conventional allograft immunity and, presumably, to recurrent autoimmune (islet-specific) pathogenesis. Importantly, CD4 T cells play a central role both in islet allograft rejection and in autoimmune disease recurrence leading to the destruction of syngeneic islet transplants in diabetic NOD mice. However, it is unclear how NOD host MHC class II (I-A(g7))-restricted, autoreactive CD4 T cells may also contribute to the recognition of allogeneic islet grafts that express disparate MHC class II molecules. We hypothesized that islet-specific CD4 T cells can target MHC-mismatched islet allografts for destruction via the "indirect" (host APC-dependent) pathway of Ag recognition. To test this hypothesis, we determined whether NOD-derived, islet-specific CD4 T cells (BDC-2.5 TCR transgenic cells) could damage MHC-mismatched islets in vivo independent of conventional allograft immunity. Results demonstrate that BDC-2.5 CD4 T cells can vigorously destroy MHC class II-disparate islet allografts established in NOD.scid recipients. Tissue injury is tissue-specific in that BDC-2.5 T cells destroy donor-type islet, but not thyroid allografts established in the same NOD.scid recipient. Furthermore, BDC-2.5 CD4 T cells acutely destroy MHC class II-deficient islet allografts in vivo, indicating that autoimmune pathogenesis can be completely independent of donor MHC class II expression. Taken together, these findings indicate that MHC-mismatched islet allografts can be vulnerable to autoimmune pathogenesis triggered by autoreactive CD4 T cells, presumably through indirect autoantigen recognition in vivo.

Steroid Avoidance in Liver Transplantation

Corticosteroids have always played a valuable role in transplantation. Unfortunately, they are subject to a wide range of side effects, such as hyperlipidemia, hypertension, diabetes mellitus, osteoporosis, growth retardation and Cushingoid appearance. Steroids may also exacerbate problems that existed before surgery, including malignancy, hepatitis B and hepatitis C. New, powerful immunosuppressants have allowed steroid use to be reduced or avoided altogether, but use of these regimens is not simple and may be associated with late acute rejection and recurrence of autoimmune disease. The present review examines the rationale for steroid avoidance in liver transplantation and assesses the new regimens that are currently being developed.

Conversion of monophasic to recurrent autoimmune disease by autoreactive T cell subsets.

Autoimmune uveitis has been elicited in susceptible rodents by several ocular-specific Ags. In most of these animal models the induced uveitis is acute and monophasic. Because recurrent uveitis poses the highest risk for blinding ocular complications in human disease, a spontaneous relapsing animal model would be most helpful in understanding the disease pathogenesis. In our current study we have observed that the adoptive transfer of interphotoreceptor retinoid-binding protein residues 1177-1191-specific T cells to naive Lewis rats induced a chronic relapsing disease, in contrast to the monophasic disease induced by immunization with interphotoreceptor retinoid-binding protein residues 1177-1191 emulsified in CFA. The chronic relapsing uveitis induced by autoreactive T cell subsets is dependent on the number of autoreactive T cells generated as well as their activation status. Our study documented a spontaneous model of recurrent uveitis in the rat, which should assist us in the study of disease pathogenesis and the design of specific therapy.

Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice.

Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.

Analogs of 1alpha,25-dihydroxyvitamin D3 as pluripotent immunomodulators.

The active form of vitamin D(3), 1,25(OH)(2)D(3), is known, besides its classical effects on calcium and bone, for its pronounced immunomodulatory effects that are exerted both on the antigen-presenting cell level as well as directly on the T lymphocyte level. In animal models, these immune effects of 1,25(OH)(2)D(3) are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH)(2)D(3) in clinical immune therapy are the adverse side effects on calcium and on bone. TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) is a structural 1,25(OH)(2)D(3) analog showing reduced calcemic activity associated with enhanced in vitro and in vivo immunomodulating capacity compared to the mother-molecule. Indeed, in vitro TX527 is more potent that 1,25(OH)(2)D(3) in redirecting differentiation and maturation of dendritic cells and in inhibiting phytohemagglutinin-stimulated T lymphocyte proliferation. In vivo, this enhanced potency of TX527 is confirmed by a stronger potential to prevent type 1 diabetes in nonobese diabetic (NOD) mice and to prolong the survival of syngeneic islets grafts, both alone and in combination with cyclosporine A, in overtly diabetic NOD mice. Moreover, these in vivo effects of TX527 are obtained without the adverse side effects observed for 1,25(OH)(2)D(3) itself. We believe therefore that TX527 is a potentially interesting candidate to be considered for clinical intervention trails in autoimmune diseases.

Impact of human leukocyte antigen matching in liver transplantation.

Human leukocyte antigen (HLA) compatibilities are beneficial in the setting of kidney transplantation but have demonstrated inconclusive results after liver transplantation. On the basis of recent controversial reports, the authors analyzed the impact of HLA matching in their patients after liver transplantation under modern immunosuppressive drug regimens and new HLA typing techniques with respect to outcome and adverse immunologic events. Data from 924 transplants with complete donor-recipient HLA typing were retrospectively analyzed. Immunosuppression was commenced as either cyclosporine A- or tacrolimus-based therapy in different protocols. The follow-up period ranged from 1 to 144.8 months (median, 66 months). The actuarial graft survival was 88% after 1 year and 78.7% after 5 years and was similar in tacrolimus- and cyclosporine A-treated patients. However, cyclosporine A-treated patients underwent significantly more rejection episodes. The number of HLA compatibilities had no influence on graft survival, whereas the number of acute rejections was significantly less in transplants with more HLA compatibilities (P<0.05). Graft survival tended to be improved in patients with chronic hepatitis B and more HLA compatibilities (P=0.05). In contrast, graft survival in transplants for primary sclerosing cholangitis was significantly impaired in the presence of one or two HLA-DR compatibilities (P<0.05). In addition, in autoimmune hepatitis, survival tended to be lower in the presence of more HLA compatibilities (P=0.1). Overall graft survival or frequency of adverse immunologic events was not influenced by any specific donor-recipient HLA allele. This study demonstrated fewer acute rejections in transplants with more HLA compatibilities. However, in liver transplantation, a more specific investigation of HLA typing may be necessary, because in some indications HLA antigens play a role in the nature of the disease. Therefore, recurrence of autoimmune disease may be more severe in patients sharing HLA antigens.