Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hered...Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).展开更多
Background：Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies （especially for the treatment of B-cell chronic lymphocytic leukemia）.However,serious infectious complications...Background：Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies （especially for the treatment of B-cell chronic lymphocytic leukemia）.However,serious infectious complications frequently occur after treatment.The reason for increased infections postalemtuzumab treatment is unknown at this stage.We explore the effect ofalemtuzumab on intestinal intraepithelial lymphocytes （IELs） and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.Methods：Twelve male cynomolguses were randomly assigned to either a treatment or control group.The treatment group received alemtuzumab （3 mg/kg,intravenous injection） while the control group received the same volume of physiological saline.Intestinal IELs were isolated from the control group and the treatment group （on day 9,35,and 70 after treatment） for counting and flow cytometric analysis.Moreover,intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.Results：The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group （0.35 ± 0.07 × 10^8 and 1.35 ± 0.09 × 10^8,respectively; P 〈 0.05） and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.In addition,the proportion ofapoptotic IELs after alemtuzumab treatment was significantly higher than in the control group （22.01 ± 3.67 and 6.01 ± 1.42,respectively; P 〈 0.05）.Moreover,the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.Conclusions：Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model.The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment.Notably,intestinal barrier function may be disrupted after alemtuzumab treatment.展开更多
Background Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody...Background Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.Methods In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients （panel reactive antibody 〉20%）. They were divided into two groups： alemtuzumab group （trial group） and anti-thymocyte globulin （ATG） group （control group）. Patients in the alemtuzumab group received intravenous alemtuzumab （15 mg） as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab （15 mg） was given. The control group received a bolus of rabbit ATG （9 mg/kg）, which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil （MMF）. Acute rejection （AR） and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. X2 test, ttest and Kaplan-Meier analysis were performed with SPSS17.0 software.Results Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar （P 〉0.05）. White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months （P 〈0.05）. One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infect展开更多
AIM To analyse the risk factors and outcomes of delayed graft function(DGF) in patients receiving a steroid sparing protocol. METHODS Four hundred and twenty-seven recipients of deceased donor kidney transplants were ...AIM To analyse the risk factors and outcomes of delayed graft function(DGF) in patients receiving a steroid sparing protocol. METHODS Four hundred and twenty-seven recipients of deceased donor kidney transplants were studied of which 135(31.6%) experienced DGF. All patients received monoclonal antibody induction with a tacrolimus based, steroid sparing immunosuppression protocol.RESULTS Five year patient survival was 87.2% and 94.9% in the DGF and primary graft function(PGF) group respectively, P = 0.047. Allograft survival was 77.9% and 90.2% in the DGF and PGF group respectively, P < 0.001. Overall rejection free survival was no different between the DGF and PGF groups with a 1 and 5 year rejection free survival in the DGF group of 77.7% and 67.8% compared with 81.3% and 75.3% in the PGF group, P = 0.19. Patients with DGF who received IL2 receptor antibody induction were at significantly higher risk of rejection in the early post-transplant period than the group with DGF who received alemtuzumab induction. On multivariate analysis, risk factors for DGF were male recipients, recipients of black ethnicity, circulatory death donation, preformed DSA, increasing cold ischaemic time, older donor age and dialysis vintage.CONCLUSION Alemtuzumab induction may be of benefit in preventing early rejection episodes associated with DGF. Prospective trials are required to determine optimal immunotherapy protocols for patients at high risk of DGF.展开更多
Background Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation （KTx）. However, curren...Background Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation （KTx）. However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue. Methods Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials （RCTs） comparing the outcome of KTx using alemtuzumab induction therapy （test group） with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio （OR） with a 95% confidence intervals （Co was the principle measurement of effect. Results Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate （ARR） was lower relative to the control （OR=0.59, 95% CI 0.34-1.01, P=0.05）. However, meta-analysis with all included studies revealed that neither ARR nor patient/graff survival rates differ significantly between the test and the control group, but the cytomegalovirus （CMV） infection rate was higher in the test group （OR 2.50, 95% CI 1.22-5.12, P=0.01）. A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs. Conclusions Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. Howeve展开更多
Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to re...Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection(AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody(thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody(basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in mostpatients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.展开更多
Alemtuzumab is a humanized mononclonal antibody known to cause rapid depletion of B-and T-cell lymphocytes. Subsequent repletion of these lymphocytes leads to changes in adaptive immunity. Alemtuzumab is approved by t...Alemtuzumab is a humanized mononclonal antibody known to cause rapid depletion of B-and T-cell lymphocytes. Subsequent repletion of these lymphocytes leads to changes in adaptive immunity. Alemtuzumab is approved by the United States Food and Drug Administration (FDA) for the treatment of B-cell lymphocytic leukemia but has been investigated off-label in recent years for treatment of autoimmune diseases, including multiple sclerosis (MS). In MS treatment, alemtuzumab is administered as pulsed therapy, given once daily initially for 5 consecutive days and then for 3 consecutive days at 12-month intervals. Alemtuzumab has recently been compared to interferon beta 1-a in one phase II and two phase III trials in patients with relapsing-remitting MS. Results from the studies show alemtuzumab compared to interferon beta 1-a is associated with a greater reduction in the risk of sustained accumulation of disability and is more effective in reducing disease relapse rates. The treatment of MS continues to be a healthcare challenge due to the modest clinical benefit and adverse effect profiles of available disease modifying treatment options. Available data suggest alemtuzumab may offer better efficacy outcomes compared to traditional disease modifying therapies in patients with MS. However, the agent has not been compared to other new disease modifying medications that have been recently introduced.展开更多
文摘Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).
基金This work was supported by grants from the National Basic Research Program （973 Program） in China （No. 2007CB513005 and 2009CB522405）, Shangdong Province Young and Middle-Aged Scientists Research Awards Fund （No. BS2011YY004）, the Key Project of National Natural Science Foundation in China （No. 30830098）, National Key Project of Scientific and Technical Supporting Programs Funded by Ministry of Science and Technology of China （No. 2008BAI60B06）, the National Natural Science Foundation in China （No. 3067206t）, the Military Scientitle Research Fund （No. 0603AM 117） and the Gut Barrier Foundation of Jie-Shou Li Academician.
文摘Background：Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies （especially for the treatment of B-cell chronic lymphocytic leukemia）.However,serious infectious complications frequently occur after treatment.The reason for increased infections postalemtuzumab treatment is unknown at this stage.We explore the effect ofalemtuzumab on intestinal intraepithelial lymphocytes （IELs） and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.Methods：Twelve male cynomolguses were randomly assigned to either a treatment or control group.The treatment group received alemtuzumab （3 mg/kg,intravenous injection） while the control group received the same volume of physiological saline.Intestinal IELs were isolated from the control group and the treatment group （on day 9,35,and 70 after treatment） for counting and flow cytometric analysis.Moreover,intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.Results：The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group （0.35 ± 0.07 × 10^8 and 1.35 ± 0.09 × 10^8,respectively; P 〈 0.05） and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.In addition,the proportion ofapoptotic IELs after alemtuzumab treatment was significantly higher than in the control group （22.01 ± 3.67 and 6.01 ± 1.42,respectively; P 〈 0.05）.Moreover,the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.Conclusions：Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model.The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment.Notably,intestinal barrier function may be disrupted after alemtuzumab treatment.
文摘Background Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.Methods In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients （panel reactive antibody 〉20%）. They were divided into two groups： alemtuzumab group （trial group） and anti-thymocyte globulin （ATG） group （control group）. Patients in the alemtuzumab group received intravenous alemtuzumab （15 mg） as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab （15 mg） was given. The control group received a bolus of rabbit ATG （9 mg/kg）, which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil （MMF）. Acute rejection （AR） and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. X2 test, ttest and Kaplan-Meier analysis were performed with SPSS17.0 software.Results Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar （P 〉0.05）. White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months （P 〈0.05）. One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infect
文摘AIM To analyse the risk factors and outcomes of delayed graft function(DGF) in patients receiving a steroid sparing protocol. METHODS Four hundred and twenty-seven recipients of deceased donor kidney transplants were studied of which 135(31.6%) experienced DGF. All patients received monoclonal antibody induction with a tacrolimus based, steroid sparing immunosuppression protocol.RESULTS Five year patient survival was 87.2% and 94.9% in the DGF and primary graft function(PGF) group respectively, P = 0.047. Allograft survival was 77.9% and 90.2% in the DGF and PGF group respectively, P < 0.001. Overall rejection free survival was no different between the DGF and PGF groups with a 1 and 5 year rejection free survival in the DGF group of 77.7% and 67.8% compared with 81.3% and 75.3% in the PGF group, P = 0.19. Patients with DGF who received IL2 receptor antibody induction were at significantly higher risk of rejection in the early post-transplant period than the group with DGF who received alemtuzumab induction. On multivariate analysis, risk factors for DGF were male recipients, recipients of black ethnicity, circulatory death donation, preformed DSA, increasing cold ischaemic time, older donor age and dialysis vintage.CONCLUSION Alemtuzumab induction may be of benefit in preventing early rejection episodes associated with DGF. Prospective trials are required to determine optimal immunotherapy protocols for patients at high risk of DGF.
文摘Background Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation （KTx）. However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue. Methods Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials （RCTs） comparing the outcome of KTx using alemtuzumab induction therapy （test group） with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio （OR） with a 95% confidence intervals （Co was the principle measurement of effect. Results Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate （ARR） was lower relative to the control （OR=0.59, 95% CI 0.34-1.01, P=0.05）. However, meta-analysis with all included studies revealed that neither ARR nor patient/graff survival rates differ significantly between the test and the control group, but the cytomegalovirus （CMV） infection rate was higher in the test group （OR 2.50, 95% CI 1.22-5.12, P=0.01）. A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs. Conclusions Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. Howeve
文摘Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection(AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody(thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody(basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in mostpatients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.
文摘Alemtuzumab is a humanized mononclonal antibody known to cause rapid depletion of B-and T-cell lymphocytes. Subsequent repletion of these lymphocytes leads to changes in adaptive immunity. Alemtuzumab is approved by the United States Food and Drug Administration (FDA) for the treatment of B-cell lymphocytic leukemia but has been investigated off-label in recent years for treatment of autoimmune diseases, including multiple sclerosis (MS). In MS treatment, alemtuzumab is administered as pulsed therapy, given once daily initially for 5 consecutive days and then for 3 consecutive days at 12-month intervals. Alemtuzumab has recently been compared to interferon beta 1-a in one phase II and two phase III trials in patients with relapsing-remitting MS. Results from the studies show alemtuzumab compared to interferon beta 1-a is associated with a greater reduction in the risk of sustained accumulation of disability and is more effective in reducing disease relapse rates. The treatment of MS continues to be a healthcare challenge due to the modest clinical benefit and adverse effect profiles of available disease modifying treatment options. Available data suggest alemtuzumab may offer better efficacy outcomes compared to traditional disease modifying therapies in patients with MS. However, the agent has not been compared to other new disease modifying medications that have been recently introduced.
