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Biomedical subjects

Hugh Auchincloss

Publications and source records attributed to Hugh Auchincloss.

At least 19 recordsLinked to original sources
PubMed2006

International trial of the Edmonton protocol for islet transplantation.

BACKGROUND: Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). METHODS: We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. RESULTS: Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. CONCLUSIONS: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Role of CXC chemokine receptor 3 pathway in renal ischemic injury.

Chemokines play a major role in the recruitment of leukocytes in inflammation and in the regulation of T helper 1 (Th1)/Th2 immune responses. These mechanisms have been recognized to be important in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The interaction of the CXC chemokine receptor 3 (CXCR3) receptor with its ligands is a key pathogenic pathway in promoting inflammation and in enhancing Th1 immune responses. After the induction of ischemia in the mouse model of renal ischemia, an increase in intrarenal expression of CXCR3 and its ligands was observed. Compared with the wild-type (WT) mice, CXCR3-deficient mice (CXCR3-/-) had significantly lower serum creatinine levels, better survival rate, and significantly less acute tubular necrosis and cellular infiltrates. In the kidney, intracellular staining of infiltrating cells that were recovered from kidneys revealed a lower percentage of CD4+IFN-gamma+ cells in the CXCR3-/- mice compared with the WT mice. Furthermore, adoptive transfer of WT CD3+ cells into CXCR3-/- mice before induction of I/R injury abrogated the protection of CXCR3-/- mice from I/R injury. It is concluded that CXCR3 plays an important role in orchestrating the recruitment of Th1 cells to the ischemic kidney and in mediating I/R injury and therefore may serve as a novel target for the therapy of I/R injury.

Analysis of Variance↗
PubMed2005

Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.

Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4(-/-) but not CD8(-/-) recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28(-/-) and a smaller proportion of CD4(-/-)CD28(-/-) mice with no effect in CD8(-/-)CD28(-/-) recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8(+) T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28(-/-) and CD8(-/-)CD28(-/-) recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-gamma-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.

Animals↗
PubMed2005

CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.

The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.

Acute Disease↗
PubMed2004

Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients.

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in renal recipients. In addition to steroids, cyclosporine A (CsA) has been implicated in contributing to increased cardiovascular risk. Conversion from CsA to tacrolimus (TAC) has been shown to improve hyperlipidemia and hypertension, but little is known about the differential effects of CsA versus TAC on other cardiovascular risk factors. We investigated overall cardiovascular risk profile after conversion from CsA to TAC. METHODS: This was an open-label, single-arm prospective study; 22 adult renal recipients who were receiving CsA-based immunosuppression with serum total cholesterol greater than 200 mg/dL more than 1 year after transplantation were enrolled. CsA was replaced by TAC. Blood pressure, fasting lipid profile, homocysteine, fibrinogen, C-reactive protein, hemoglobin A1c, and creatinine were measured at baseline and at 3 and 6 months after conversion. RESULTS: There was a significant improvement in fibrinogen (366 +/- 81 - 316 +/- 65 mg/dL, P <0.001), total cholesterol (250 +/- 50 - 207 +/- 29 mg/dL, P <0.001), and low-density lipoprotein cholesterol (155 +/- 43 - 121 +/- 24 mg/dL, P <0.001) after conversion. No new onset or worsening of diabetes mellitus was observed after conversion. There were no significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, hemoglobin A1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required before and after conversion. CONCLUSIONS: Our results indicate that conversion to low-dose TAC may be preferable over CsA for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.

Adult↗
PubMed2004

Depleting anti-CD4 monoclonal antibody cures new-onset diabetes, prevents recurrent autoimmune diabetes, and delays allograft rejection in nonobese diabetic mice.

BACKGROUND: The prevention of recurrent autoimmunity is a prerequisite for successful islet transplantation in patients with type I diabetes. Therapies effective in preserving pancreatic beta-cell mass in patients with newly diagnosed diabetes are good candidates for achieving this goal. Anti-CD3 monoclonal antibody (mAb) and antilymphocyte antisera are the only therapies to date that have cured early diabetic disease in the nonobese diabetic (NOD) mouse. We investigated whether other immunosuppressive therapies, including short-term depleting anti-CD4 mAb or costimulation blockade, would affect the disease progression in recently diabetic NOD mice. We also evaluated the effect of the anti-CD4 mAb on syngeneic and allogeneic graft survival in diabetic NOD recipients. METHODS AND RESULTS: We demonstrate that a short course of anti-CD4 mAb early after hyperglycemia onset cured diabetes. Normal islets and islets with CD4+ and CD8+ T-cell peri-insulitic infiltrate were found in the pancreata of cured NOD mice. A similar regimen prevented the recurrence of autoimmune diabetes in NOD/severe combined immunodeficient disease (SCID) islet isografts and delayed the rejection of allogeneic C57BL/6 islet allografts in diabetic female NOD mice. The co-transfer of diabetogenic splenocytes with splenocytes from anti-CD4 mAb-treated and cured NOD mice into 7-week-old, irradiated, NOD male mice was not able to protect from diabetes occurrence. This indicates that an anti-CD4-mediated cure of diabetes is independent of the induction of immunoregulatory T cells. Anti-CD154 mAb and cytotoxic T-lymphocyte antigen 4 immunoglobulin were ineffective in early-onset diabetes. CONCLUSION: Our results provide the first evidence that newly established autoimmune islet destruction in NOD mice responds to a short course of anti-CD4 mAb. In contrast, costimulation blockade is ineffective in this clinically relevant model.

Adoptive Transfer↗
PubMed2004

Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo.

Chemokines have a pivotal role in the mobilization and activation of specific leukocyte subsets in acute allograft rejection. However, the role of specific chemokines and chemokine receptors in islet allograft rejection has not been fully elucidated. We now show that islet allograft rejection is associated with a steady increase in intragraft expression of the chemokines CCL8 (monocyte chemoattractant protein-2), CCL9 (monocyte chemoattractant protein-5), CCL5 (RANTES), CXCL-10 (IFN-gamma-inducible protein-10), and CXCL9 (monokine induced by IFN-gamma) and their corresponding chemokine receptors CCR2, CCR5, CCR1, and CXCR3. Because CCR2 was found to be highly induced, we tested the specific role of CCR2 in islet allograft rejection by transplanting fully MHC mismatched islets from BALB/c mice into C57BL/6 wild-type (WT) and CCR2-deficient mice (CCR2-/-). A significant prolongation of islet allograft survival was noted in CCR2-/- recipients, with median survival time of 24 and 12 days for CCR2-/- and WT recipients, respectively (p < 0.0001). This was associated with reduction in the generation of CD8+, but not CD4+ effector alloreactive T cells (CD62L(low)CD44(high)) in CCR2-/- compared with WT recipients. In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR). However, these changes were only transient in CCR2-/- recipients that ultimately rejected their grafts. Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival. This study demonstrates the important role for CCR2 in early islet allograft rejection and highlights the tissue specificity of the chemokine/chemokine receptor system in vivo in regulating allograft rejection.

Animals↗
PubMed2004

Mechanism of action of donor-specific transfusion in inducing tolerance: role of donor MHC molecules, donor co-stimulatory molecules, and indirect antigen presentation.

Donor-specific transfusion (DST) can synergize with T cell co-stimulatory blockade in inducing tolerance in several transplant models, but the mechanism of action of DST is poorly characterized. This study used genetically altered mice in an established model of cardiac transplantation to study the role of MHC and co-stimulatory molecule expression on DST cells in mediating the immunomodulatory effects of DST. In addition, to examine the role of indirect antigen presentation in the effect of DST, experiments used recipient mice that do not express MHC class II molecules on peripheral antigen-presenting cells, but do have functional CD4(+) T cells (II(-)4(+)). As previously reported, treatment with DST from wild-type donors in combination with CD154 blockade induced tolerance in wild-type recipients of cardiac allografts. Tolerance in this model is also induced despite the absence of MHC class I and II, CD40, or B7 molecules on transfused cells. In contrast, eliminating the indirect pathway using II(-)4(+) recipients blocked the induction of long-term cardiac allograft survival by DST. These results indicate that the indirect antigen recognition pathway mediates the immunomodulatory effect of DST in inducing transplantation tolerance in vivo.

Animals↗
PubMed2004

Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response.

BACKGROUND: Xenografts of islets from organ-cultured fetal pig pancreases transplanted into non-immunosuppressed mice are rejected within 10 days. Immunosuppression with anti-T cell (anti-CD4) monoclonal antibody alone delays rejection of these xenografts for about 28 days, but rejection eventually occurs despite marked depletion of T cells. To determine if the critical CD4+ T cells responsible for xenograft islet rejection function through the direct or indirect pathway, selective class II-deficient mice that express class II antigens only on their thymic epithelium (not on peripheral cells) with normal numbers of CD4+ T cells, (class II-, CD4+), were used as recipients of xenograft islets to test if rejection occurs in the absence of an indirect response. METHODS: Control (C57BL/6) or class II-, CD4+ mice were transplanted under the kidney capsule with cultured fetal pig islets. Class II-, CD4+ mice have normal numbers of B cells, CD4+, gamma delta T cells, and slightly increased numbers of CD8+ T cells. Additional mice were thymectomized before receiving anti-CD4 or anti-CD8 monoclonal antibodies. Islet graft survival was determined histologically as fetal pig islets were too immature to secrete insulin. RESULTS: Xenograft survival in control animals was 7 to 14 days. In contrast, graft survival in class II-, CD4+ mice was significantly prolonged to greater than 35 days. Depletion of CD8+ T cells in class II-, CD4+ mice prolonged graft survival to about 70 days. Depletion of CD4+ T cells from these mice further prolonged xenograft survival to about 100 days. CONCLUSIONS: These results suggest that the rejection of pig islets by mice initially depends on a CD4 dependent indirect response. The CD4 direct response also contributes to graft destruction. CD8+ T cells also participate in graft destruction, albeit weakly.

Animals↗
PubMed2003

A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients.

BACKGROUND: Delayed graft function (DGF) is frequently observed in recipients of cadaveric renal transplants. Previous retrospective or nonrandomized studies have suggested that intraoperative administration of polyclonal antithymocyte preparations may reduce the incidence of DGF, possibly by decreasing ischemia-reperfusion injury. METHODS: We performed a prospective randomized study of Thymoglobulin induction therapy in adult cadaveric renal transplant recipients. Between January 2001 and January 2002, 58 adult cadaveric renal transplant recipients were randomized to receive intraoperative or postoperative Thymoglobulin induction therapy. Three to six doses of Thymoglobulin (1 mg/kg/dose) were administered during the first week posttransplant. Baseline immunosuppression consisted of tacrolimus (54 of 58) or cyclosporine A (4 of 58), steroids, and mycophenolate mofetil. DGF was defined by the requirement for hemodialysis within the first week posttransplant. RESULTS: There were no significant differences between the two groups in recipient demographics, donor age, cold ischemia time, or total number of doses of Thymoglobulin administered. Intraoperative Thymoglobulin administration was associated with significantly less DGF and a lower mean serum creatinine on postoperative days 10 and 14 (P<0.05). Posttransplant length of stay was also significantly shorter for the intraoperative Thymoglobulin patient group. The acute rejection rate was also lower in the intraoperative treatment group but this did not achieve statistical significance. There was no difference in the incidence of cytomegalovirus disease between the two groups. CONCLUSIONS: The results of this study indicate that intraoperative Thymoglobulin administration, in adult cadaveric renal transplant recipients, is associated with a significant decrease in DGF, better early allograft function in the first month posttransplant, and a decreased posttransplant hospital length of stay.

Acute Disease↗
PubMed2003

The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Animals↗
PubMed2003

Pig islet xenografts are resistant to autoimmune destruction by non-obese diabetic recipients after anti-CD4 treatment.

In addition to providing a large source of donor tissue, xenogeneic islet transplantation might avoid recurrent autoimmunity in patients with type 1 diabetes. To examine this possibility further, xenogeneic pig islets were transplanted into recipient mice in the presence or absence of autoimmunity. Spontaneously, non-obese diabetic (NOD) recipients rejected isografts rapidly whether or not the recipients were depleted of CD4+ T-cells. Young NOD mice made diabetic with streptozotocin accepted islet isografts without immunosuppression, indicating that destructive autoimmunity did not develop in these recipients. Pig xenografts were rejected equally quickly in the two types of NOD recipients in the absence of immunosuppression and survived for up to 9 weeks in both types of NOD recipients after CD4 depletion. BALB/c mice often accepted pig xenografts indefinitely after anti-CD4 antibody treatment. These results suggest that pig islets are resistant to recurrent autoimmunity when CD4+ T-cells are depleted. The difficulty in obtaining indefinite islet xenograft survival in NOD recipients occurs independently from the development of destructive autoimmunity.

Animals↗
PubMed2003

Further analysis of the T-cell subsets and pathways of murine cardiac allograft rejection.

The present study examined the role of CD4+ and CD8+ T cells in cardiac allograft rejection when either the direct or indirect pathway was eliminated for the CD4+ portion of the response. To study the pathways in vivo, we used genetically altered mouse strains that lack class II antigens as either the donors or recipients for cardiac transplantation. In contrast to earlier published studies, which used different strain combinations, we found that either CD4- or CD8-depletion prolonged cardiac allograft survival moderately, but not indefinitely, in an MHC-mismatched, minor-matched combination. When the CD4+ indirect pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present and when either CD4+ or CD8+ T cells were depleted. When the CD4+ direct pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present, there was slow rejection when CD4+ T cells were eliminated, and no rejection was seen for more than 100 days when CD8+ T cells were eliminated. However, the long-surviving allografts on the recipients with only CD4+ cells and an indirect pathway did show evidence of chronic vasculopathy. Thus, either CD4+ or CD8+ T cells can mediate acute cardiac allograft rejection in these experiments when both pathways are available. In addition, CD4+ T cells can provide help for acute rejection through either the direct or indirect pathway. Finally, recipients who have only CD4+ cells and an indirect pathway do not demonstrate acute rejection, but do show evidence of chronic rejection.

Animals↗
PubMed2003

Acute humoral rejection in hepatitis C-infected renal transplant recipients receiving antiviral therapy.

The use of interferon-alpha (IFN) in hepatitis C (HCV)-infected renal recipients has been associated with acute rejection and graft loss. We reviewed our recent experience in HCV (+) renal recipients treated with antiviral therapy for biopsy proven chronic hepatitis C. Twelve HCV (+) recipients who recently received antiviral therapy were analyzed. Post-treatment sera were tested for donor-specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of initiating antiviral therapy, two of 12 patients (17%) developed acute rejection, which was characterized as acute humoral rejection (de novo DSA in serum and C4d deposits in peritubular capillaries). Both progressed to graft failure. Nine of the remaining 10 patients tested did not have DSA. The use of IFN was associated with severe acute humoral rejection (C4d +, DSA +). The recognition of IFN-associated acute humoral rejection in this series may explain the high rate of graft loss reported previously in renal recipients receiving IFN.

Adult↗
PubMed2003

Allorecognition and effector pathways of islet allograft rejection in normal versus nonobese diabetic mice.

Islet transplantation is becoming an accepted therapy to cure type I diabetes mellitus. The exact mechanisms of islet allograft rejection remain unclear, however. In vivo CD4(+) and CD8(+) T cell-depleting strategies and genetically altered mice that did not express MHC class I or class II antigens were used to study the allorecognition and effector pathways of islet allograft rejection in different strains of mice, including autoimmunity-prone nonobese diabetic (NOD) mice. In BALB/c mice, islet rejection depended on both CD4(+) and CD8(+) T cells. In C57BL/6 mice, CD8(+) T cells could eventually mediate islet rejection by themselves, but they produced rejection more efficiently with help from CD4(+) T cells stimulated through either the direct or indirect pathway. In C57BL/6 mice, CD4(+) T cells alone caused islet rejection when only the direct pathway was available but not when only the indirect pathway was available. In contrast, in NOD mice, CD4(+) T cells alone, with only the indirect pathway, could mediate islet and cardiac allograft rejection. These findings indicate that different mouse strains can make use of different pathways for T cell-mediated rejection of islet allografts. In addition, they demonstrate that NOD mice, which develop autoimmunity and are known to be resistant to tolerance induction, have an unusually powerful CD4(+) cell indirect mechanism that can cause rejection of both islet and cardiac allografts. These data shed light on the mechanisms of islet allograft rejection in different responder strains, including those with autoimmunity.

Animals↗
PubMed2002

Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4(+) T cells: evidence from a lymphopenic T cell model.

While intrathymic MHC expression influences the specificity of developing thymocytes, we considered that peripheral MHC expression might influence the reactivity of postthymic T cells. We now report for CD4(+) T cells that peripheral MHC-II expression does influence their reactivity and self-tolerance. Upon transfer into MHC-II-deficient lymphopenic hosts, mature CD4(+) T cells were found to acquire an activated memory phenotype and to become: (1) autoreactive against syngeneic MHC-II(+) skin grafts, (2) hyperreactive against third-party MHC-II(+) skin grafts, and (3) functionally dysregulated, resulting in a lymphoproliferative disorder characterized by intraepithelial infiltrations. Peripheral MHC-II expression appeared to influence CD4(+) T cell reactivity by two complementary mechanisms: maintenance of CD4(+)CD25(+) regulatory T cells ("suppression") and direct dampening of CD4(+) T cell reactivity ("tuning").

Adoptive Transfer↗