The Experts below are selected from a list of 126 Experts worldwide ranked by ideXlab platform
Carl-gustav Groth - One of the best experts on this subject based on the ideXlab platform.
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New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection
BioDrugs, 1997Co-Authors: Lars Wennberg, Carl-gustav GrothAbstract:Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, Gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, Gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune β cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.
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New immunosuppressive drugs and their role in the prevention of islet xenograft rejection.
BioDrugs : clinical immunotherapeutics biopharmaceuticals and gene therapy, 1997Co-Authors: Lars Wennberg, Carl-gustav GrothAbstract:Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, Gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation.
Reinhard Hohlfeld - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Approaches in Multiple Sclerosis
BioDrugs, 2002Co-Authors: Heinz Wiend, Reinhard HohlfeldAbstract:The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent immunobiological findings and current pathophysiological concepts together with advances in biotechnology, improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established immunomodulatory therapies (e.g. interferon-β and glatiramer acetate), there have been a remarkable number of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even turned out to have unexpectedly severe adverse effects. Although to date there is no uniformly accepted model for MS, there is agreement on the significance of inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the individual steps of a hypothetical pathogenetic cascade. Crucial corners like: (i) the prevalence and peripheral activation of CNS-autoreactive T cells in the periphery; (ii) adhesion and penetration of T cells into the CNS; (iii) local activation and proliferation and; (iv) de-and remyelination processes can be targeted through their putative mediators. Like a ‘specificity pyramid’, therapeutic approaches therefore cover from general immunosuppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex. We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include cytokine modulators [tumour necrosis factor (TNF)-α antagonists, interleukin-10, interleukin-4, transforming growth factor-β2], immunosuppressive agents (roquinimex, Gusperimus, sulfasalazine, cladribine), inducers of remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3, anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis). The main conclusions that can be drawn from these ‘negative’ experiences are as follows. Theoretically promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unforeseen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up (e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFα blockers; oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine; bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mechanisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing understanding of multiple sclerosis, ‘misses’ are nearly as important to the scientific process as the ‘hits’.
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Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials.
BioDrugs : clinical immunotherapeutics biopharmaceuticals and gene therapy, 2002Co-Authors: Heinz Wiendl, Reinhard HohlfeldAbstract:The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent immunobiological findings and current pathophysiological concepts together with advances in biotechnology, improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established immunomodulatory therapies (e.g. interferon-beta and glatiramer acetate), there have been a remarkable number of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even turned out to have unexpectedly severe adverse effects. Although to date there is no uniformly accepted model for MS, there is agreement on the significance of inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the individual steps of a hypothetical pathogenetic cascade. Crucial corners like: the prevalence and peripheral activation of CNS-autoreactive T cells in the periphery;adhesion and penetration of T cells into the CNS;local activation and proliferation and;de- and remyelination processes can be targeted through their putative mediators. Like a 'specificity pyramid', therapeutic approaches therefore cover from general immunosuppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex. We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include cytokine modulators [tumour necrosis factor (TNF)-alpha antagonists, interleukin-10, interleukin-4, transforming growth factor-beta2], immunosuppressive agents (roquinimex, Gusperimus, sulfasalazine, cladribine), inducers of remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3, anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis). The main conclusions that can be drawn from these 'negative' experiences are as follows. Theoretically promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unforeseen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up (e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFalpha blockers; oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine; bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mechanisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing understanding of multiple sclerosis, 'misses' are nearly as important to the scientific process as the 'hits'.
Lars Wennberg - One of the best experts on this subject based on the ideXlab platform.
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New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection
BioDrugs, 1997Co-Authors: Lars Wennberg, Carl-gustav GrothAbstract:Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, Gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, Gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune β cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.
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New immunosuppressive drugs and their role in the prevention of islet xenograft rejection.
BioDrugs : clinical immunotherapeutics biopharmaceuticals and gene therapy, 1997Co-Authors: Lars Wennberg, Carl-gustav GrothAbstract:Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, Gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation.
Antonio Tarantino - One of the best experts on this subject based on the ideXlab platform.
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Promising new agents in the prevention of transplant rejection.
Drugs in R&D, 1999Co-Authors: Claudio Ponticelli, Antonio TarantinoAbstract:Promising immunosuppressive drugs designed to prevent rejection have been developed recently. Two monoclonal antibodies directed against the interleukin-2 (IL-2) receptor, daclizumab and basiliximab, have been shown to significantly reduce the incidence of acute rejection without increasing adverse events. Sirolimus (rapamycin), an agent that inhibits T- and B-response at a later stage than cyclosporin, has been shown to be synergistic with cyclosporin in experimental and clinical studies. Ongoing clinical trials have reported that in renal transplantation high doses of sirolimus are as effective as cyclosporin. SDZ-RAD, a derivative of sirolimus, is also under investigation. FTY-720 another promising drug, prolonged the survival of allografts and synergised with cyclosporin and sirolimus in experimental models. Gusperimus (deoxyspergualin), which inhibits IL-1 synthesis, was useful in reversing early and late acute rejection in clinical trials. Antisense oligonucleotides which interfere with intercellular adhesion molecules which are important in rejection, gave encouraging results in primate renal allografts.
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Promising New Agents in the Prevention of Transplant Rejection
Drugs in R & D, 1999Co-Authors: Claudio Ponticelli, Antonio TarantinoAbstract:Promising immunosuppressive drugs designed to prevent rejection have been developed recently. Two monoclonal antibodies directed against the interleukin-2 (IL-2) receptor, daclizumab and basiliximab, have been shown to significantly reduce the incidence of acute rejection without increasing adverse events. Sirolimus (rapamycin), an agent that inhibits T- and B-response at a later stage than cyclosporin, has been shown to be synergistic with cyclosporin in experimental and clinical studies. Ongoing clinical trials have reported that in renal transplantation high doses of sirolimus are as effective as cyclosporin. SDZ-RAD, a derivative of sirolimus, is also under investigation. FTY-720 another promising drug, prolonged the survival of allografts and synergised with cyclosporin and sirolimus in experimental models. Gusperimus (deoxyspergualin), which inhibits IL-1 synthesis, was useful in reversing early and late acute rejection in clinical trials. Antisense oligonucleotides which interfere with intercellular adhesion molecules which are important in rejection, gave encouraging results in primate renal allografts. The availability of these new drugs will be able to further abate the risk of rejection in organ transplantation. However, caution is warranted with their use in order to avoid the risks of over immunosuppression. Today excellent results can be obtained with the available drugs. Newer immunosuppressive schedules should be designed, not only to reduce the risk of rejection, but also to obtain a better therapeutic index that allows a further improvement of the graft survival while minimising the comorbidity and drug-related toxicity.
Tomokazu Shimizu - One of the best experts on this subject based on the ideXlab platform.
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clinicopathologic analysis of acute vascular rejection cases after renal transplantation
Transplantation proceedings, 2012Co-Authors: Tomokazu Shimizu, Hideki Ishida, Kazuya Omoto, Tatsu Tanabe, Kazunari TanabeAbstract:Abstract Introduction Histopathologic change of acute vascular rejection (AVR) is characterized by intimal arteritis and transmural arteritis. In this report, we discuss the clinicopathologic analysis of AVR cases after renal transplantation. Patients AVR was diagnosed in 28 renal transplant recipients followed up in our institute between January 2003 and November 2010. Results Among 28 cases of AVR, 18 were mild (v1 in Banff 07 classification), 8 were moderate (v2), and 2 were severe (v3). Interstitial inflammation was present in 25 biopsy specimens. Moderate to severe tubulitis (t2–t3) was present in 10 biopsy specimens and transplant glomerulitis in 17; peritubular capillaritis was in 25 of the 28 biopsy specimens. C4d deposition in peritubular capillaries was observed in 11/28 cases. By using assays with plastic beads coated with human leukocyte antigen (HLA) in the 28 cases, we detected circulating anti-HLA alloantibody in 18 patients, among which 11/28 were donor-specific. Acute antibody-mediated rejection was diagnosed in 6 cases. Among AVR cases, 19/28 displayed steroid-resistant rejection (SRR) requiring greater anti-rejection therapy (ART), including muromonab CD3 injection, Gusperimus injections, plasmapheresis, intravenous immune globulin, and/or rituximab injections. Twenty of 28 patients recovered renal allograft function after ART, and 26/28 grafts are functioning. Among the 2 cases of graft loss, only 1 patient lost his graft due to AVR. Conclusions In some cases, AVR might be provoked by anti-donor antibodies. The prognosis of the graft exhibiting AVR was relatively good using available immunosuppression.
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clinicopathological analysis of acute vascular rejection cases after renal transplantation
Clinical Transplantation, 2010Co-Authors: Tomokazu Shimizu, T Tokumoto, Kuniko Tsunoyama, Hideki Ishida, H Shirakawa, Kazuya Omoto, Kazunari TanabeAbstract:Shimizu T, Ishida H, Shirakawa H, Omoto K, Tsunoyama K, Tokumoto T, Tanabe K. Clinicopathological analysis of acute vascular rejection cases after renal transplantation. Clin Transplant 2010: 24 (Suppl. 22): 22–26. © 2010 John Wiley & Sons A/S. Abstract: Histopathological change of acute vascular rejection (AVR) is characterized by intimal arteritis and transmural arteritis. In this report, we discuss the clinicopathological analysis of AVR cases after renal transplantation (RTX). Patients: AVR was diagnosed in 17 patients from 17 renal transplant patients followed in our institute between January 2003 and September 2008. We retrospectively reviewed these 17 patients. Results: Among 17 cases of AVR, 10 cases were mild (v1 in Banff 07 classification), five were moderate (v2), and two were severe (v3). Interstitial inflammation (i1–i3) was present in all 17 biopsies. Moderate to severe tubulitis (t2–t3) was present in seven biopsies, and transplant glomerulitis (g1–g3) was present in 11, peritubular capillaritis (ptc1–ptc3) was in 15 of 17 biopsies. C4d deposition in peritubular capillary (PTC) was observed in 6 of 17 cases. By assaying with plastic beads coated with anti-human leukocyte antigen (HLA) antigen performed in 17 cases, the circulating ant-HLA alloantibody was detected in 10 patients, of which 5/10 were donor-specific antibodies (DSA). Acute antibody-mediated rejection (AAMR) was diagnosed in three cases. Many of v1 cases, steroid pulse therapy (SP) were effective. In v2 and v3 cases, six of seven were steroid-resistant rejection and were need more anti-rejection therapy (ART), such as muromonab CD3 (OKT3) injection, Gusperimus (DSG) injection, plasmapheresis, intravenous immune globulin, and injection of rituximab. Ten of 17 patients recovered their renal allograft functions by ART, and 16 of 17 patients’ grafts are functioning. Deterioration of renal allografts’ function after biopsies was seen in seven patients with one of them lost their graft. Conclusions: In some cases, AVR might be provoked by anti-donor antibodies. The prognosis of the graft exhibiting AVR was relatively good in present immunosuppression and ART.
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Clinicopathological analysis of acute vascular rejection cases after renal transplantation.
Clinical transplantation, 2010Co-Authors: Tomokazu Shimizu, T Tokumoto, Kuniko Tsunoyama, Hideki Ishida, H Shirakawa, Kazuya Omoto, Kazunari TanabeAbstract:Histopathological change of acute vascular rejection (AVR) is characterized by intimal arteritis and transmural arteritis. In this report, we discuss the clinicopathological analysis of AVR cases after renal transplantation (RTX). AVR was diagnosed in 17 patients from 17 renal transplant patients followed in our institute between January 2003 and September 2008. We retrospectively reviewed these 17 patients. Among 17 cases of AVR, 10 cases were mild (v1 in Banff 07 classification), five were moderate (v2), and two were severe (v3). Interstitial inflammation (i1-i3) was present in all 17 biopsies. Moderate to severe tubulitis (t2-t3) was present in seven biopsies, and transplant glomerulitis (g1-g3) was present in 11, peritubular capillaritis (ptc1-ptc3) was in 15 of 17 biopsies. C4d deposition in peritubular capillary (PTC) was observed in 6 of 17 cases. By assaying with plastic beads coated with anti-human leukocyte antigen (HLA) antigen performed in 17 cases, the circulating ant-HLA alloantibody was detected in 10 patients, of which 5/10 were donor-specific antibodies (DSA). Acute antibody-mediated rejection (AAMR) was diagnosed in three cases. Many of v1 cases, steroid pulse therapy (SP) were effective. In v2 and v3 cases, six of seven were steroid-resistant rejection and were need more anti-rejection therapy (ART), such as muromonab CD3 (OKT3) injection, Gusperimus (DSG) injection, plasmapheresis, intravenous immune globulin, and injection of rituximab. Ten of 17 patients recovered their renal allograft functions by ART, and 16 of 17 patients' grafts are functioning. Deterioration of renal allografts' function after biopsies was seen in seven patients with one of them lost their graft. In some cases, AVR might be provoked by anti-donor antibodies. The prognosis of the graft exhibiting AVR was relatively good in present immunosuppression and ART.
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a case of acute vascular rejection after overseas deceased kidney transplantation
Clinical Transplantation, 2007Co-Authors: Tomokazu Shimizu, Kazunari Tanabe, T Tokumoto, Kuniko Tsunoyama, Hideki Ishida, Hiroshi Kobayashi, Kentaro Masumoto, Junpei Iizuka, Shun Ichi Kajimoto, Yutaka YamaguchiAbstract:A 54-yr-old Japanese male received overseas deceased kidney transplantation in January 2006. His allograft functioned immediately and he received immunosuppression with cyclosporine A (CyA), mycophenolate mofetil (MMF), and prednisone (PR). On day 24 after transplantation, he came back to Japan. His serum creatinine level (s-Cr) was 1.39 mg/dL at two months after transplantation when he was admitted into Toda Central General Hospital on March 2006, for follow-up his renal allograft. He had taken only two immunosuppressive drugs, MMF and PR, and had not taken CyA at that time. His serum creatinine gradually rose after hospitalization. Allograft biopsy performed on April 6, 2006, showed acute vascular rejection (Banff 97 acute/active cellular rejection Grade III), together with suspicious for acute humoral rejection (Banff 97 antibody-mediated rejection Grade II). After treatment of two courses of steroid pulses and five d of Gusperimus, acute vascular rejection and acute humoral rejection were relieved, which had been proven by the third allograft biopsy. In conclusion, this was a case of acute vascular rejection after overseas deceased kidney transplantation, resulted from non-compliance with immunosuppressive therapy.
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a case of acute humoral rejection with various depositions of c4d igg igm and c3c in peritubular capillaries and or glomerular capillaries
Clinical Transplantation, 2005Co-Authors: Tomokazu Shimizu, Hiroshi Toma, Kazunari Tanabe, T Tokumoto, Izumi Kanemitsu, Kuniko Tsunoyama, Hideki Ishida, N Ishikawa, Yutaka YamaguchiAbstract:A 41-year-old Japanese male patient with end-stage renal disease received ABO compatible living related kidney transplantation from his sister on April 2003. The kidney functioned immediately after kidney transplantation.Protocol allograft biopsy at 1 yr after kidney transplantation was performed on April 2004. His serological data was not particular and he did not suffer with chronic inflammation. The allograft biopsy specimen revealed moderate accumulations of polymorphonuclear leukocytes in peritubular capillaries (PTCs), dilatation of PTCs and moderate infiltrations of polymorphonuclear and/or mononuclear cell in glomeruli (Transplant glomerulitis, moderate). Immunofluorescent study (IF) of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial-staining pattern in PTCs for C4d. The C4d was also strongly detected in a linear glomerular basement membrane (GBM) pattern. And widespread moderate C3c deposits, weak IgM, and IgG deposits were also seen in PTCs. Immunofluorescent study also showed granularly peripheral and mesangial deposits of strong IgM, Clq, and moderate IgG in glomeruli, IgA and C3c were faintly positive. The panel reactive antibody, which had been negative before transplantation, was positive for both HLA classes I and II at that time. We diagnosed as acute humoral rejection (AHR) and he was treated with course of steroid pulses and 5 d of Gusperimus (DSG); and a total of three times Plasma exchange (PE) treatment was added. The level of serum creatinine, once increased to 1.7 mg/dL, decreased gradually to 1.4 mg/dL. He has a stable graft function.This is the only case of various depositions of immunoglobulins and complements in PTC and/or glomerular capillaries during AHR.