SangStat Medical Corporation

We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation.

A direct role of carbon monoxide (CO), an effector-signaling molecule during heme oxygenase-1 (HO-1) catalysis of heme, in the protection against hepatic ischemia/reperfusion (I/R) injury needs to be established. This study was designed to determine the effects and downstream mechanisms of CO on cold I/R injury in a clinically relevant isolated perfusion rat liver model. After 24 hours of cold storage, rat livers perfused ex vivo for 2 hours with blood supplemented with CO (300 parts per million) showed significantly decreased portal venous resistance and increased bile production, as compared with control livers perfused with blood devoid of CO. These beneficial effects correlated with improved liver function (serum glutamic oxaloacetic transaminase levels) and diminished histological features of hepatocyte injury (Banff's scores). The CO-mediated cytoprotective effects were nitric oxide synthase- and cyclic guanine monophosphate-independent, but p38 mitogen-activated protein kinase (MAPK)-dependent. Moreover, adjunctive use of zinc protoporphyrin, a competitive HO-1 inhibitor, has shown that exogenous CO could fully substitute for endogenous HO-1 in preventing hepatic I/R insult. This study performed in a clinically relevant ex vivo cold ischemia model is the first to provide the evidence that HO-1-mediated cytoprotection against hepatic I/R injury depends on the generation of, and can be substituted by, exogenous CO. The p38 MAPK signaling pathway represents the key downstream mechanism by which CO prevents the I/R insult. In conclusion, regimens that employ exogenous CO should be revisited, as they may have potential applications in preventing/mitigating I/R injury, and thus expanding the liver donor pool for clinical transplantation.

Delayed graft function (DGF) is the need for dialysis in the first week after transplantation. Studied were risk factors for DGF in adult (age >/=16 yr) cadaveric renal transplant recipients by means of a multivariable modeling procedure. Only donor and recipient factors known before transplantation were chosen so that the probabilities of DGF could be calculated before transplantation and appropriate preventative measures taken. Data on 19,706 recipients of cadaveric allografts were obtained from the United States Renal Data System registry (1995 to 1998). Graft losses within the first 24 h after surgery were excluded from the analysis (n = 89). Patients whose DGF information was missing or unknown (n = 2820) and patients missing one or more candidate predictors (n = 2951) were also excluded. By means of a multivariable logistic regression analysis, factors contributing to DGF in the remaining 13,846 patients were identified. After validating the logistic regression model, a nomogram was developed as a tool for identifying patients at risk for DGF. The incidence of DGF was 23.7%. Sixteen independent donor or recipient risk factors were found to predict DGF. A nomogram quantifying the relative contribution of each risk factor was created. This index can be used to calculate the risk of DGF for an individual by adding the points associated with each risk factor. The nomogram provides a useful tool for developing a pretransplantation index of the likelihood of DGF occurrence. With this index in hand, better informed treatment and allocation decisions can be made.

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.

BACKGROUND: Ischemia/reperfusion (I/R) injury is one of the most important causes of the early graft loss. We have shown that overexpression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32, protects rat livers against I/R injury. We report on the cytoprotective effects of HO-1 in a rat cardiac I/R injury model, using cobalt protoporphyrin (CoPP) as HO-1 inducer and zinc protoporphyrin (ZnPP) as HO-1 inhibitor. METHODS: Three groups of Lewis rats were studied: group 1 control donors received phosphate-buffered saline 48 hr before the harvest; group 2 donors were pretreated with CoPP at -48 hr; and in group 3, donors received CoPP at -48 hr and ZnPP was given to recipients at reperfusion. Hearts were harvested, stored in University of Wisconsin solution (4 degrees C) for 24 hr, and then transplanted to syngeneic (Lewis) rats. RESULTS: Sixty percent of control grafts ceased their function in <15 min. In contrast, 80% of CoPP-pretreated grafts survived 14 days. All grafts stopped functioning within 24 hr after CoPP + ZnPP therapy. Cardiac HO-1 enzymatic activity and protein expression correlated with beneficial effects of CoPP and deleterious effects of adjunctive ZnPP treatment. Markedly less apoptotic (TUNEL+) myocyte/endothelial cells could be detected in CoPP cardiac grafts, as compared with controls. The expression of antiapoptotic (Bcl-2/Bag-1) proteins was up-regulated in the CoPP group. CONCLUSION: HO-1 overexpression provides potent protection against cold I/R injury in a stringent rat cardiac model. This effect depends, at least in part, on HO-1-mediated up-regulation of a host antiapoptotic mechanism, especially in the early postreperfusion period.

BACKGROUND: Ischemia/reperfusion (I/R) injury is a critical factor in the dysfunction of steatotic orthotopic liver transplants. Heme oxygenase-1 (HO-1), a cytoprotective protein, may be important in ameliorating hepatic I/R injury. METHODS: We used adenovirus (Ad)-based HO-1 gene transfer to analyze the effects of HO-1 overexpression in a well-established fatty Zucker rat model of I/R followed by orthotopic liver transplantation. RESULTS: Ad-HO-1 gene therapy increased recipient survival (80% vs. 40-50% in controls) and significantly diminished hepatocyte injury, as compared with untreated and Ad-beta-galactosidase (Ad-beta-Gal)-treated livers. Orthotopic liver transplants in the Ad-HO-1 group exhibited less macrophage infiltration in the portal areas, as compared with controls. Unlike untreated and Ad-beta-Gal-treated orthotopic liver transplant controls, which showed elevated levels of inducible nitric oxide synthase by infiltrating macrophages, inducible nitric oxide synthase expression in the Ad-HO-1 group was almost absent. In contrast, endothelial nitric oxide synthase was comparable in Ad-HO-1- and Ad-beta-Gal-transduced fatty orthotopic liver transplants. Intragraft expression of antiapoptotic Bcl-2 and Bag-1 was increased in Ad-HO-1-treated orthotopic liver transplants, as compared with Ad-beta-Gal controls. Moreover, increased HO enzymatic activity was accompanied by inhibition of caspase-3 protein expression. CONCLUSIONS: HO-1 gene transfer significantly prolongs survival of steatotic orthotopic liver transplants, depresses macrophage infiltration, suppresses local expression of inducible nitric oxide synthase, and modulates pro- and antiapoptotic pathways.

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases and the prevention of infections and of graft versus host reactions in recipients of allogeneic bone marrow transplants. The immunomodulatory effects of IVIg are largely dependent on their ability to interact with membrane molecules of lymphocytes. We report here that IVIg recognizes the B07.75-84 peptide, corresponding to a conserved region of the alpha I helix of the first domain of HLA-B7 01, which represents a nonpolymorphic determinant of HLA class I molecules. Intact IVIg and its F(ab')2 fragments bound to the peptide as well as to purified soluble HLA and to HLA on a human T cell line. Binding of IVIg to HLA was assessed by ELISA, immunofluorescence, and real-time analysis of the interaction using the BIAlite system. The binding of antipeptide antibodies to HLA was inhibited by free peptide. Antipeptide antibodies isolated from IVIg by affinity chromatography inhibited CD8 cell-mediated cytotoxicity of an influenza virus-specific human T cell line. The presence in IVIg of antibodies to critical regions of HLA class 1 molecules suggests a possible role for IVIg in modulation of class-I-restricted cellular interactions in the immune response.

Apoptosis via the CD95/FasL (CD95L) pathway plays an important role in allograft rejection. Heme oxygenase 1 (HO-1), a stress-responsive cytoprotective molecule, may be essential in preventing graft rejection. We used Ad-HO-1 gene transfer to analyze HO-1-mediated effects in a rat allogeneic orthotopic liver transplantation (OLT) model. The cytotoxicity to Fas-bearing YAC-1 target cells and frequency of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive (TUNEL(+)) cells in vitro were diminished in Ad-CD95L + Ad-HO-1-transfected cells, as compared with Ad-CD95L + Ad-beta-gal controls (p < 0.001). AdHO-1 gene transfer prevented <10-day rejection of dark agouti (DA) livers in Lewis (LEW) rats (survival >32 days), and diminished apoptosis. Unlike Ad-beta-gal OLTs, which showed signs of severe acute rejection, OLTs in the Ad-HO-1 group exhibited mild to moderate rejection and improved function. These beneficial effects were abrogated after adjunctive treatment with tin protoporphyrin (SnPP), an HO-1 antagonist. Intragraft expression of HO-1 and antiapoptotic gene products (Bcl-xl/Bag-1) was enhanced in Ad-HO-1-transduced OLTs, in association with selectively depressed expression of helper T cell type 1 cytokines (interleukin 2 and interferon gamma), as compared with Ad-beta-gal controls. To deliver CO, one of the downstream HO-1 mediators, allogeneic OLT recipients were exposed to methylene chloride. Such treatment prolonged survival to >47 days, diminished apoptosis, and preserved hepatic architecture/function. Thus, Ad-HO-1 gene transfer prevents CD95/FasL-mediated apoptosis, and significantly prolongs allogeneic OLT survival via a downstream HO-1-CO signaling pathway.

BACKGROUND: RDP58 is a novel anti-inflammatory d-amino acid decapeptide that inhibits synthesis of proinflammatory cytokines by disrupting cell signaling at the pre-MAPK MyD88-IRAK-TRAF6 protein complex. We therefore evaluated its efficacy and safety in parallel multicenter, double-blind, randomized concept studies in ulcerative colitis (UC). METHODS: In the first trial, 34 patients with mild to moderate active UC were randomized (1:2) to placebo (n = 13) or RDP58 100 mg (n = 21). In the second trial, 93 similar patients were randomized (1:1:1) to placebo (n = 30) RDP58 200 mg (n = 31), or RDP 300 mg (n = 32). In both studies, treatment success was defined as a simple clinical colitis activity index score of no more than 3 at 28 days. Sigmoidoscopy and rectal biopsy (at baseline and 28 days) and safety measures (baseline and 28 and 56 days) were other endpoints. RESULTS: Treatment success on RDP 100 mg was 29% versus 46% on placebo (P = 0.46). There were no significant differences in sigmoidoscopy or histology score. In the second study, treatment success on the higher doses of RDP58 (200 and 300 mg) was 71% and 72%, respectively, versus 43% on placebo (P = 0.016). Improvements in sigmoidoscopy scores (41% on 200 mg and 46% on 300 mg versus 32% on placebo) did not reach significance, but histology scores improved significantly (P = 0.002) versus placebo. Overall, adverse events were no different between placebo (3.3 +/- 2.4) and RDP58 (2.7 +/- 1.4, 300-mg group). CONCLUSIONS: RDP58 at a dose of 200 or 300 mg, but not 100 mg, was effective in mild-to-moderate UC. RDP58 was safe and well tolerated, and its novel action makes it an attractive potential therapy.

Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid, an agent that inhibits the proliferation of B and T lymphocytes through noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently, mycophenolate mofetil is approved for the prevention of acute renal allograft rejection when given in combination with cyclosporine and steroids. Several studies also demonstrated that the agent is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection as well.

BACKGROUND: The aim of this study was to demonstrate that 3-days of induction immunosuppression with thymoglobulin was as effective and safe as a 7-day course and reduced initial hospitalization after transplantation. METHODS: This was a prospective, nonrandomized trial of 40 consecutive patients receiving thymoglobulin induction for 3 days and followed for 1 year. An historical group of 48 patients that received 7 days of thymoglobulin served as controls. RESULTS: At 1 year, acute rejection (5 vs. 4%), graft survival (95 vs. 98%) and patient survival were similar; a composite end point of freedom from death, rejection, or graft loss, the event-free graft survival, was similar as was the safety profile. In the 3-day group, lymphocyte depletion was more sustained and initial hospitalization was significantly shorter (6 vs. 8 days). CONCLUSION: Three-day induction with thymoglobulin is as effective and safe as seven days, decreases initial hospitalization and causes more sustained lymphocyte depletion.

This is the first report on suppression of immune effector functions following upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyrin (CoPP)-induced HO-1 expression on cell-mediated immune responses. Administration of CoPP to CBA mice resulted in overexpression of HO-1 in the spleen, liver and kidneys. In vitro measurements of T cell-mediated and NK-cell-mediated cytotoxicity in spleens from CoPP-treated animals demonstrated a severe suppression of their effector functions while administration of Zn-PP or vitamin B12 had no effect. Furthermore, CoPP therapy decreased the lymphoproliferative alloresponse and differentiation of cytotoxic T cells. Inhibition of proliferation appeared to be due to cell growth arrest with an increased number of cells staying in G0/G1 phase. Despite the suppressed proliferative response, IL-2 production in the MLR was not inhibited. In contrast, CoPP decreased the production of IL-10, IFN-gamma and TNF-alpha. In vivo, CoPP prolonged the survival of heterotopic heart allografts in mice. The immunosuppressive effects following CoPP-mediated upregulation of HO-1 were similar to those observed after peptide-mediated upregulation of HO-1. The results indicate that overexpression of HO results in the inhibition of several immune effector functions and thus provides an explanation for stress-induced immunosuppression.

T cell recognition of MHC molecules initiates a cascade of events resulting in allograft rejection. CTLs damage the graft by targeting nonself-MHC class I molecules. We and others have previously shown that small synthetic peptides corresponding to regions of certain MHC class I molecules can inhibit the CTL response against MHC class I alloantigens in vitro. Here we report that rat heart allografts survived survived indefinitely when transplanted into recipients treated with a synthetic peptide corresponding to residues 75-84 of (B7.75-84) in combination with a subtherapeutic dose of cyclosporine A. Furthermore, this treatment induced long-term donor-specific tolerance that was mediated by anergic cells, indicating that such peptides may have potential as therapeutics for human organ transplantation.

Abstract Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, exhibits potent antioxidant and anti-inflammatory properties. We developed HO-1 transgenic (Tg) mice using a rat HO-1 genomic transgene under the control of the endogenous promoter. Transgene expression was demonstrated by RT-PCR in all studied tissues, and a modest HO-1 overexpression was documented by Western, ELISA, and enzyme activity assays. To assess the effect of local vs systemic HO-1 in the acute rejection response, we used Tg mice as organ donors or recipients of MHC-incompatible heart grafts. In the local HO-1 overexpression model, Tg allografts survived 10.5 ± 0.7 days (n = 10), compared with 6.5 ± 0.4 days (n = 6) for wild-type donor controls (p = 0.0001). In the systemic HO-1 overexpression model, Tg recipients maintained allografts for 26.8 ± 3.4 days (n = 10), compared with 6.3 ± 0.1 days (n = 12) in wild-type controls (p = 0.00009). Inhibition of HO activity by treatment with tin protoporphyrin blunted survival advantage in Tg mice and resulted in acute graft rejection (n = 3). Increased carboxyhemoglobin levels were consistently noted in Tg mice. Comparisons of grafts at day 4 indicated that HO-1 overexpression was inversely associated with vasculitis/inflammatory cell infiltrate in both models. Hearts transplanted into Tg recipients showed decreased CD4+ lymphocyte infiltration and diminished immune activation, as judged by CD25 expression. Thus, although local and systemic HO-1 overexpression improved allograft outcomes, systemic HO-1 led to a more robust protection and resulted in a significant blunting of host immune activation. This Tg mouse provides a valuable tool to study mechanisms by which HO-1 exerts beneficial effects in organ transplantation.

SangStat Medical Corp., Menlo Park, California, Department of Surgery, University of Wisconsin Hospital, Madison, Wisconsin; and Department of Cardiothoracic Surgery, Stanford University, Stanford, California 1SangStat Medical Corp. 3Department of Surgery, University of Wisconsin Hospital 4Department of Cardiothoracic Surgery, Stanford University

Whereas αβ T cell receptors (TCR) recognize processed antigenic peptides or glycolipids bound respectively to major histocompatibility complex or CD1 molecules, γδ TCR react differently to a broad set of native antigens. A major human γδ T cell subset is activated through a mechanism involving Vγ 9Vδ 2 TCR and structurally unrelated phosphorylated nonpeptide antigens (referred to as phosphoantigens). Here, the structure‐function relationship of the strongest natural and synthetic phosphoantigens stimulating γδ cells was analyzed to elucidate the molecular basis of this unconventional recognition. Besides conformational determinants, we found that chemical reactivity of antigens is critical to their bioactivity. For Vγ 9Vδ 2 T cell activation, both organic and phosphorylated moieties of strong ligands undergo rapid and degradative structural changes. Conversely, analogs that are resistant to degradation specifically antagonize phosphoantigen‐mediated γδ T cell activation. These data suggest a novel mode of antigen perception involving both topological recognition and ligand consumption, which confers highly specific γδ T cell activation by structurally diverse ligands.

Identification of risk factors influencing graft survival may lead to the development of models to predict graft outcome. Such models may provide guidance for immunosuppressive therapy, measure posttransplantation outcome, and eventually improve graft survival in high-risk patients. A major risk factor influencing graft survival is allosensitization. However, due to the lack of standardization of lymphocytotoxicity assays, the detection of alloantibodies utilizing this current methodology may not correlate with posttransplant events. Recently, a novel standardized enzyme-linked immunosorbent assay (ELISA) for the detection of anti-HLA class I IgG antibodies was developed. To evaluate the predictive value of this diagnostic test, a retrospective analysis of 124 renal allograft recipients with an 18-month follow-up time was performed. A highly significant (P=0.01) correlation between pre-transplant ELISA panel reactive antibody (PRA) results and graft loss was observed. Patients with pre-transplant ELISA PRA of >10% had a three times higher risk of graft loss compared with patients who tested negative. No such correlation was observed with complement-dependent cytotoxicity results independent of the reduction of IgM antibodies with dithiothreitol. Similarly, a highly significant correlation of ELISA results with the occurrence of early graft dysfunction was observed. Almost all patients (88%) with a pretransplant ELISA PRA of >50% required posttransplant dialysis, compared with 45% of patients with a pretransplant ELISA PRA of 10-50% and 27% of patients with a pretransplant ELISA PRA of <10%. No such difference was observed with complement-dependent cytotoxicity %PRA values. Analysis of posttransplant specimens by ELISA demonstrated a strong correlation of assay results with graft rejection and graft dysfunction. In summary, these results suggest that detection of anti-HLA class I antibodies by ELISA identifies patients at high risk for graft loss. No other single risk factor of such magnitude has been identified so far.

Allospecific T lymphocytes mediate graft rejection through specific, direct or indirect, recognition of processed determinants of foreign MHC class I molecules. Small synthetic peptides derived from highly conserved sequences of the alpha 1 helix of the first domain of certain MHC class I molecules have been shown to inhibit CTL responses in vitro and to prolong graft survival in rats when combined with subtherapeutic doses of cyclosporine. Here, we report that the survival of LEW.1W heart allografts was significantly prolonged when transplanted into congenic LEW.1A recipients treated only with a peptide corresponding to residues 75-84 of the human HLA-B7-01 molecule (B7.75-84) before transplantation. The experimental value for mean survival time (+/- SD) in untreated recipients was 13 +/- 6 days and in peptide-treated recipients was 42 +/- 27 days (P < 0.002). A total of 64% of treated recipients had a functioning graft at 30 days, while grafts were rejected in all rats belonging to the control group within this time. Within graft-infiltrating leukocytes (GIL) in B7.75-84-treated animals, the proportion of T cells was significantly lower and that of CD5-/TCR alpha beta-/CD16-/CD8+ and MHC class II+ cells concomitantly increased, as compared with nontreated animals. GIL from B7.75-84-treated animals also exhibited a dramatic decrease (approximately 70%) of allospecific and spontaneous (NK) cytotoxic activity, whereas their proliferation and IL-2 production were similar in both experimental groups. The IFN-gamma, IL-2, and IL-10 mRNA levels from GIL from peptide-treated recipients were similar to levels of controls, reflecting a state of activation of GIL. Perforin and granzyme A mRNA, the level of which may be modulated parallel to impaired cytotoxic functions, were at similar levels in both experimental groups. These data demonstrate that B7.75-84 significantly prolongs graft survival in LEW.1A rats when given as a single agent and suggests that a specifically decreased cytotoxic response (allospecific and spontaneous) plays a major role.

PURPOSE: In interstitial cystitis (IC) inflammation induces and perpetuates neurotrophic changes in the bladder, resulting in the symptoms of frequency, urgency and pain. RDP58 (NH2-arg-norleucine (nle)-nle-arg-nle-nle-nle-gly-tyr-CONH2) (Sangstat Corp., Fremont, California) is a novel synthetic peptide that inhibits early signal transduction pathways for the expression of inflammatory cytokines. In this study we evaluated the effects of intravesical RDP58 on an established model of cystitis. MATERIALS AND METHODS: Mice were catheterized and equal volumes of Escherichia coli lipopolysaccharide (LPS) or saline were instilled into the bladder. After 45 minutes the bladders were drained and distilled water or RDP58 (1 mg/ml) was instilled for 30 minutes. At 24 hours later the bladders were excised and cultured for analysis of tumor necrosis factor-alpha (TNF-alpha), substance P (SP) and nerve growth factor (NGF) production, as quantified by enzyme-linked immunosorbent assay. RESULTS: LPS caused severe inflammation in mouse bladders compared with controls. Exposure to LPS increased the levels of TNF-alpha, SP and NGF production compared with controls (each p <0.05). In LPS exposed mice RDP58 significantly decreased inflammatory parameters by 82% 24 hours after treatment (p <0.05). Within 4 hours RDP58 abolished TNF-alpha production and at 24 hours TNF-alpha remained undetectable. RDP58 also significantly decreased SP and NGF production in LPS exposed bladders by more than 40% and 85%, respectively (each p <0.05). CONCLUSIONS: Inflammatory models of cystitis result in increased levels of TNF-alpha, SP and NGF production in the bladder, paralleling the hypothesized neuro-inflammatory etiology of IC. RDP58 decreases inflammation and neurotrophic factors in vivo and it may potentially treat bladder disorders with an inflammatory component, such as IC.

BACKGROUND: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria is controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. METHODS: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. RESULTS: Average Medicare payments for renal transplant recipients in the three years after transplantation increased from 60,436 dollars per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to 80,807 dollars for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P<0.001). By three years after transplantation, the average Medicare payments were 64,119 dollars for transplantations of kidneys with less than 12 hours of cold ischemia time and 74,997 dollars for those with more than 36 hours (P<0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings (4,290 dollars per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold ischemia time were considered. CONCLUSIONS: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold ischemia time were greater than the advantages of optimizing HLA matching.