Biomedical subjects

Barry D Kahan

Publications and source records attributed to Barry D Kahan.

At least 19 recordsLinked to original sources

PubMed2006

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

BACKGROUND: Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. METHODS: This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. RESULTS: FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. CONCLUSIONS: While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

Adult↗

PubMed2006

Pancreas transplantation utilizing thymoglobulin, sirolimus, and cyclosporine.

BACKGROUND: This study aims to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimune response of pancreas-kidney transplant recipients. METHODS: Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. Ten recipients were also enrolled in a study to measure immune responsiveness. Flow PRA determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed during the first posttransplant year. RESULTS: One-year patient, kidney, and pancreas graft survivals were 97%, 94%, and 92%, respectively. There was one death and three graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study (n=10) displayed>80% depression of CD3, CD4, and CD8 (+) cell counts up to 3 months posttransplant. At transplantation 9/10 patients displayed<10% class I and no class II HLA antibody. By 3 months, 7/10 monitored recipients showed a transient elevation in class I HLA antibodies, including 2 patients who expressed>80% Flow PRA. One patient was pretransplant FCXM positive, whereas by 3 months posttransplant 2/10 patients demonstrated a positive FCXM. There were no clinical consequences of the presence of HLA antibody or the positive FCXMs. By 6 months, 7/9 patients demonstrated immunoregulatory suppressor cells. CONCLUSIONS: The absence of acute rejection events was likely due to inhibition of donor-specific immunity by the immunosuppressive regimen. Seventy percent of patients demonstrated an early, non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the monitored patients displayed immunoregulatory cells probably contributing to the successful outcomes.

Adult↗

PubMed2006

Allograft rejection requires STAT5a/b-regulated antiapoptotic activity in T cells but not B cells.

STATs play key roles in immune function. We examined the role of STAT5a/b in allograft rejection. STAT5a/b-deficient mice showed a 4-fold increased survival time of heart allografts (p < 0.01). Unlike wild type, purified STAT5a/b-/- T cells transferred to Rag1-/- recipients failed to mediate heart allograft rejection until supplemented with STAT5a/b-/- B cells. In vitro, STAT5a/b-/- T cells did not proliferate in response to Con A or alloantigens but entered apoptosis within 48 h (95%). Activated STAT5a/b-/- T cells showed increased expression of proapoptotic (caspases, DNA repair genes, TNF/TNFR-associated factor family genes) and decreased antiapoptotic mRNAs in microarrays, while Western blots confirmed reduced antiapoptotic Bcl-2 and elevated proapoptotic Bax protein expression. Interestingly, at 24 h postactivation, STAT5a/b+/+ and STAT5a/b-/- T cells produced similar levels of IL-2, IL-4, IL-10, and IFN-gamma mRNA; ELISPOT assay showed an equivalent number of IL-4- and IFN-gamma-producing T cells in both STAT5a/b+/+ and STAT5a/b-/- splenic populations. Sera from STAT5a/b+/+ and STAT5a/b-/- rejectors had donor-specific IgM, IgG1, IgG2a, and IgG2b Ab, while STAT5a/b deficiency had no impact on B cell survival or proliferation in response to LPS. Compared with allografts from STAT5a/b+/+ recipients, heart allografts from STAT5a/b-/- recipients had markedly reduced infiltration by CD4 and CD8 T cells but increased infiltration by B cells and dense endothelial deposition of C4d, a marker of humoral rejection. Thus, activated STAT5a/b-/- T cells produce cytokines prior to entering apoptosis, thereby promoting differentiation of B cells yielding donor-specific IgM and IgG Ab that mediate allograft rejection.

Adoptive Transfer↗

PubMed2006

A comparative study of sirolimus tablet versus oral solution for prophylaxis of acute renal allograft rejection.

This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus t(max) after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus C(min,TN) and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Administration, Oral↗

PubMed2005

Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.

BACKGROUND: Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. METHODS: A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. RESULTS: The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. CONCLUSIONS: Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.

Everolimus↗

PubMed2005

The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities.

JAK3 is a cytoplasmic tyrosine kinase with limited tissue expression but is readily found in activated T cells. Patients lacking JAK3 are immune compromised, suggesting that JAK3 represents a therapeutic target for immunosuppression. Herein, we show that a Mannich base, NC1153, blocked IL-2-induced activation of JAK3 and its downstream substrates STAT5a/b more effectively than activation of the closely related prolactin-induced JAK2 or TNF-alpha-driven NF-kappaB. In addition, NC1153 failed to inhibit several other enzymes, including growth factor receptor tyrosine kinases, Src family members, and serine/threonine protein kinases. Although NC1153 inhibited proliferation of normal human T cells challenged with IL-2, IL-4, or IL-7, it did not block T cells void of JAK3. In vivo, a 14-day oral therapy with NC1153 significantly extended survival of MHC/non-MHC mismatched rat kidney allografts, whereas a 90-day therapy induced transplantation tolerance (>200 days). Although NC1153 acted synergistically with cyclosporin A (CsA) to prolong allograft survival, it was not nephrotoxic, myelotoxic, or lipotoxic and did not increase CsA-induced nephrotoxicity. In contrast to CsA, NC1153 was not metabolized by cytochrome P450 3A4. Thus, NC1153 prolongs allograft survival without several toxic effects associated with current immunosuppressive drugs.

Animals↗

PubMed2005

Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients.

BACKGROUND: Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects. METHODS: We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone. RESULTS: Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes. CONCLUSIONS: The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.

Adolescent↗

PubMed2005

FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.

BACKGROUND: FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation. METHODS: This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up. RESULTS: The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation. CONCLUSIONS: FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.

Adolescent↗

PubMed2005

Clinical application of sirolimus in renal transplantation: an update.

In addition to an analysis of the final results of phase I/II and phase III clinical trials of sirolimus (SRL), this review focuses on the recent results of several studies in renal transplantation, which include diverse combinations of SRL with other immunosuppressive agents. While SRL was initially introduced as an adjunctive agent to calcineurin inhibitors, it is now serving as the base for therapies that spare or avoid these nephrotoxic drugs. However, to optimize the use of SRL as base therapy, further work is necessary to determine target concentrations, requirement for concomitant steroids and/or nucleoside synthesis blockers, and countermeasure therapy to overcome the drug's adverse effects.

Cyclosporine↗

PubMed2004

Phase I and phase II safety and efficacy trial of intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302) for the prevention of acute allograft rejection.

BACKGROUND: ISIS 2302, an antisense oligonucleotide that inhibits the expression of human intercellular adhesion molecule (ICAM)-1, was evaluated in combination with a cyclosporine (CsA)-prednisone (Pred) regimen first in a phase I safety and pharmacokinetic study and then in a phase II assessment of prophylaxis of acute rejection episodes in deceased donor renal allografts. METHODS: Both phase I and phase II trials were double-blinded and placebo-controlled, including 17 stable and 39 de novo patients, respectively, in time-lagged, ascending-dose regimens. Each study compared the outcomes of 8 alternate-day intravenous infusions of four ISIS 2302 dose levels (0.05, 0.5, 1.0, or 2.0 mg/kg) versus placebo (3:1 ratio). Patients were followed for 34 days (phase I) or 6 months (phase II). All transplant patients were followed for 3 years. RESULTS: ISIS 2302 produced no evident toxicity; a significant, dose-related increase in activated partial thromboplastin time was accompanied by a trend toward a decreased platelet count. ISIS 2302 did not alter the pharmacokinetic behavior of CsA. At 6 months, the rates of acute rejection episodes were 38.1% in the ISIS 2302 group versus 20.0% in the placebo group. Three-year graft survivals were similar. The mean creatinine values at 1, 2, and 3 years for all ISIS dose groups combined versus placebo over 3 years showed no significant differences. CONCLUSIONS: ISIS 2302 did not evoke side-effects and produced slightly improved renal function. However, in this pilot study, it did not further reduce the rate of acute rejection episodes or increase graft survival compared to a concentration-controlled CsA-Pred regimen.

Creatinine↗

PubMed2004

The selective use of basiliximab versus thymoglobulin in combination with sirolimus for cadaveric renal transplant recipients at low risk versus high risk for delayed graft function.

BACKGROUND: We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes. METHODS: We retrospectively reviewed 145 cadaveric renal allograft recipients who received either basiliximab (n=115) or thymoglobulin (n=30) in combination with sirolimus and prednisone, followed by delayed introduction of reduced doses of cyclosporine. Recipients were stratified as high immune responders if they were African American, a retransplant recipient, or a recipient with a panel-reactive antibody greater than 50%. All other recipients were considered low immune responders. RESULTS: Basiliximab-treated high immune responders exhibited a higher incidence of acute rejection episodes (26%) than either basiliximab-treated low immune responders (10%, P=0.04) or thymoglobulin-treated high immune responders (3%, P=0.01). The median time to initiation of cyclosporine was 12 days; cyclosporine was initiated when the serum creatinine level was 2.5 mg/dL or less. Patients with early return of renal function displayed a lower incidence of acute rejection episodes than those with later recovery of function (P=0.003). High immune responders treated with basiliximab expressed a higher mean serum creatinine level at 3 months (P<0.01), 6 months (P=0.02) and 12 months (P=0.01) than either low immune responders treated with basiliximab or high immune responders treated with thymoglobulin. CONCLUSION: A strategy combining sirolimus with basiliximab for low-immunologic risk recipients and thymoglobulin for high-risk recipients leads to prompt recovery of renal function with a low risk of acute rejection episodes.

Adult↗

PubMed2004

FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.

Adolescent↗

PubMed2004

Metabolic interaction between cyclosporine and sirolimus.

BACKGROUND: When the immunosuppressants cyclosporine (CsA) and sirolimus (SRL) are co-administered to transplant patients, lower doses are used than when either drug is given alone. Since both drugs share similar transport and metabolic pathways, there is the potential for an interaction leading to unpredictable effects. Furthermore, both drugs affect the activity of cytochrome P450 3A1/2 (CYP3A1/2), the rat parallel to human CYP3A4, and the multidrug transporter P-glycoprotein (Pgp). METHODS: To clarify the role of metabolic enzymes and membrane transporters involved in the disposition of both drugs, we examined hepatic CYP3A1/2, Pgp, and multidrug resistance gene (mdr) mRNA during chronic therapy with CsA and SRL in salt-depleted rats. Specifically, rats were given intravenous doses of CsA 2.5 mg/kg and SRL 1 mg/kg, alone or in combination, for two weeks via constant rate intravenous infusion. RESULTS: CsA treatment inhibited hepatic CYP3A1/2 protein expression, catalytic activity, and mRNA levels. SRL dosing suppressed CYP3A1/2 protein expression and catalytic activity, without affecting mRNA. With combined dosing, however, there was a much greater reduction. Hepatic Pgp protein levels were elevated after treatment with either drug alone, as well as with combined dosing. Compared to controls, there were significant increases in mdr1a and mdr1b mRNA levels in all treatment groups, with the combined drugs causing the greatest increase. CONCLUSIONS: Both CYP3A1/2 and Pgp participate in the disposition of CsA and SRL in rats. Changes in the individual activities of CYP3A1/2 and Pgp may contribute to an interaction between CsA and SRL resulting in unanticipated effects during chronic therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results.

BACKGROUND: Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell-depleting and interleukin-2 receptor antibodies. METHODS: A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. RESULTS: At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell-depleting antibody induction (36.1%) when compared with those receiving anti-interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). CONCLUSIONS: Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell-depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.

Antibodies, Monoclonal↗

PubMed2004

Toward calcineurin antagonist minimization.

Explore the source record for details and available documents.

Calcineurin Inhibitors↗

PubMed2004

Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines.

Binding of the P-, L-, and E-selectins to sialyl Lewis(x) (sLe(x)) retards circulating leukocytes, thereby facilitating their attachment to the blood vessels of allografts. Whether the selectin inhibitor bimosiamose (BIMO; C(46)H(54)O(16) . 0.25 H(2)O [867.4 molecular weight]) inhibits the rejection process of kidney allografts in a rat model was examined. Rat recipients acutely rejected kidney allografts at a mean survival time of 8.8 +/- 0.75 d. An intravenous 7-d infusion by osmotic pump of 2.5, 5, 10, or 20 mg/kg BIMO extended kidney allograft survival to 11.5 +/- 2.2 d (P < 0.03), 25.4 +/- 11.4 d (P < 0.006), 37.4 +/- 13.6 d (P < 0.001), and 39.8 +/- 34.5 d (P < 0.01), respectively. Combination of BIMO with cyclosporine produced synergistic interactions, as documented by the combination index (CI) values of 0.34 to 0.43 (CI <1 is synergistic; CI = 1 is additive; and CI >1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI = 0.64) and FTY720 (CI = 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4(+), CD8(+), and macrophages on day 7 after grafting was observed. Multiple cytokines were also expressed, including IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-alpha, and IFN-gamma in kidney allografts on days 3, 5, and 7 after grafting, as measured by a ribonuclease protection assay. Furthermore, at similar time points, BIMO treatment reduced intragraft expression of P-selectin glycoprotein ligand-1, CX(3)CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.

Animals↗

PubMed2004

Janus kinase 3: a novel target for selective transplant immunosupression.

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.

Amino Acid Sequence↗

PubMed2003

Selection of lowly immunogenic and highly tolerogenic donor and recipient allochimeric class I major histocompatibility complex proteins.

BACKGROUND: Ten different highly polymorphic amino acids (AAs) are located in the alpha1 (alpha1h) and alpha2 (alpha2h) helical regions of the class I major histocompatibility complex RT1. An rat alloantigen. We examined the potential of alpha1h-RT1. An versus alpha2h-RT1. An polymorphic AAs to induce accelerated rejection or tolerance of heart allografts. METHODS: The allochimeric alpha1h52-90n-RT1.Ac and alpha2h148-179n-RT1.Ac cDNAs were produced by the substitution of nucleotides encoding recipient RT1.Ac AAs for donor RT1. An AAs. Allochimeric and wild-type (WT)-RT1. An proteins were generated in an Escherichia coli expression system. RESULTS: A single portal vein administration of 100 mug alpha1h52-90n-RT1.Ac protein in combination with a 7-day course of oral cyclosporine A (4 mg/kg) induced tolerance to Brown Norway (BN) (RT1n) heart allografts in PVG (RT1c) recipients more effectively than did WT-RT1. An protein; alpha2h148-179n-RT1.Ac protein was ineffective. However, subcutaneous injection of 100 mug WT-RT1. An (but neither alpha1h52-90n-RT1.Ac nor alpha2h148-179n-RT1.Ac) protein induced accelerated rejection of BN heart allografts. Untreated PVG recipients of BN heart allografts displayed activation of both interleukin (IL)-2- and interferon-gamma-producing T helper (Th) 1 cells and IL-4- and IL-10-producing Th2 cells on days 5, 7, and 14 postgrafting, as measured by an enzyme-linked immunospot assay. In contrast, in comparison with rejectors, tolerant recipients showed down-regulation of Th1 cells and up-regulation of Th2 cells on days 5, 7, 14, and 200 postgrafting. Histology of heart allografts showed that tolerant BN heart allografts had no evidence of acute or chronic rejection when examined on day 100 after transplantation. CONCLUSIONS: The poorly immunogenic alpha1h52-90n-RT1.Ac allochimeric protein induces tolerance by selective activation of regulatory Th2 cells.

Animals↗