The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
G Cambridge - One of the best experts on this subject based on the ideXlab platform.
-
repeated b Lymphocyte Depletion with rituximab in rheumatoid arthritis over 7 yrs
Rheumatology, 2006Co-Authors: C Popa, M J Leandro, G Cambridge, Jcw EdwardsAbstract:Objective To assess safety and efficacy of repeated B-cell Depletion with rituximab in patients with rheumatoid arthritis (RA). Methods Thirty-seven patients with refractory RA entered into a programme of repeated B-Lymphocyte Depletion (up to 5 cycles, 89 cycles in total) with protocols based on the anti-CD20 monoclonal antibody, rituximab, have been observed over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Results Twenty two subjects have been followed up for >5 yrs. Average duration of benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximab +/- cyclophosphamide (cy) carcinomata have developed as follows: breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunoglobulin levels to below the normal range occurred in 12 patients for IgM (undetectable levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunoglobulin levels before the first cycle. Conclusion Repeated B-Lymphocyte Depletion over a 5-yr period appears to be an acceptable and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunoglobulin levels require surveillance.
-
b Lymphocyte Depletion in rheumatoid arthritis targeting of cd20
Current directions in autoimmunity, 2005Co-Authors: Jonathan C W Edwards, M J Leandro, G CambridgeAbstract:Background: During the 1990s evidence emerged to suggest that B Lymphocyte Depletion in rheumatoid arthritis (RA) might be of major benefit. Methods and Results: In 1997 the B lympholytic monoclonal
-
b Lymphocyte Depletion therapy with rituximab in rheumatoid arthritis
Rheumatic Diseases Clinics of North America, 2004Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B Lymphocyte Depletion therapy in rheumatoid arthritis can provide major clinical benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. Rituximab is a highly effective agent, but it may be best used in combination with other agents. Substantial improvement following a single course of therapy has been found to last up to 42 months, and it is reasonable to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.
-
serologic changes following b Lymphocyte Depletion therapy for rheumatoid arthritis
Arthritis & Rheumatism, 2003Co-Authors: G Cambridge, Jonathan C W Edwards, M J Leandro, Michael R Ehrenstein, Martin Salden, M D Bodmansmith, Anthony D B WebsterAbstract:Objective To explore the changes in serologic variables and clinical disease activity following B Lymphocyte Depletion in 22 patients with rheumatoid arthritis (RA). Methods B Lymphocyte Depletion was attained using combination therapy based on the monoclonal anti-CD20 antibody rituximab. Levels of a serologic indicator of inflammation, C-reactive protein (CRP), of antimicrobial antibodies, of autoantibodies including IgA-, IgM-, and IgG-class rheumatoid factors (RF), and of antibodies to cyclic citrullinated peptide (anti-CCP) were assayed. Results The majority of patients showed a marked clinical improvement after treatment with rituximab, with benefit lasting up to 33 months. Levels of total serum immunoglobulins fell, although the mean values each remained within the normal range. Whereas the IgM-RF response paralleled the changes in total serum IgM levels, the levels of IgA-RF, IgG-RF, and IgG and anti-CCP antibodies decreased significantly more than did those of their corresponding total serum immunoglobulin classes. The kinetics for the reduction in CRP levels also paralleled the decreases in autoantibody levels. In contrast, levels of antimicrobial antibodies did not change significantly. B Lymphocyte return occurred up to 21 months posttreatment. The time to relapse after B Lymphocyte return was often long and unpredictable (range 0–17 months). Relapse was, however, closely correlated with rises in the level of at least one autoantibody. Increased autoantibody levels were rarely observed in the absence of clinical change. Conclusion Following B Lymphocyte Depletion in patients with RA, a positive clinical response occurred in correlation with a significant drop in the levels of CRP and autoantibodies. Antibacterial antibody levels were relatively well maintained. B Lymphocyte return preceded relapse in all patients. There was also a temporal relationship between clinical relapse and rises in autoantibody levels. Although these observations are consistent with a role for B Lymphocytes in the pathogenesis of RA, the precise mechanisms involved remain unclear.
-
an open study of b Lymphocyte Depletion in systemic lupus erythematosus
Arthritis & Rheumatism, 2002Co-Authors: M J Leandro, G Cambridge, Jonatha C W Edwards, Michael R Ehrenstei, David A IsenbergAbstract:Objective To gain preliminary evidence for the safety and efficacy of B Lymphocyte Depletion therapy in refractory systemic lupus erythematosus (SLE). Methods Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-label basis. During a 2-week period, each patient received two 500-mg infusions of rituximab, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. Results No significant adverse events were observed during followup. Patient 1 had not improved at 3 months but was then lost to followup. At 6 months, all 5 remaining patients had improved, as evidenced by improvement in British Isles Lupus Assessment Group global scores, from a median of 14 (range 9–27) at baseline to a median of 6 (range 3–8) at 6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. Hemoglobulin levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation rate decreased in patients 2, 3, 4, and 5 and was stable in patient 1. In patients 4 and 5, the urinary protein–to-creatinine ratio decreased significantly. C3 serum levels increased in all 5 patients who had low levels at baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. The variation in the level of anti–double-stranded DNA antibody was different in individual patients. Conclusion This study provides sufficient evidence for the safety and possible efficacy of B Lymphocyte Depletion therapy in SLE to justify a formal controlled trial.
Michael R Bishop - One of the best experts on this subject based on the ideXlab platform.
-
infectious complications after unrelated donor allogeneic hematopoietic cell transplantation with or without alemtuzumab based in vivo Lymphocyte Depletion
Blood, 2013Co-Authors: Andrew Flynn, Ronald E Gress, Michael R Bishop, Juan Geabanacloche, Rachel B Salit, Frances T Hakim, David Moorshead, Zach Powell, Jennifer Hsu, Steven Z PavleticAbstract:The addition of alemtuzumab to conditioning may decrease the incidence of graft versus host disease (GVHD) after unrelated donor (URD) allogeneic hematopoietic cell transplantation (alloHCT) but may also contribute to impaired pathogen immunity due to donor Lymphocyte Depletion. We identified and graded infections occurring within 6 months after URD alloHCT in 78 individuals treated either with (N=40) or without (N=38) alemtuzumab during alloHCT for hematologic cancers. Conditioning included fludarabine (120 mg/m2 total) and cyclophosphamide (4,800 mg/m2 total) over 4 days with either alemtuzumab (100 mg total days -8 to -4) followed by cyclosporine (AC) or with tacrolimus, methotrexate, and sirolimus (TMS) based GVHD prophylaxis. Both groups received a filgrastim mobilized peripheral blood graft from an 8/8 or 7/8 HLA-matched unrelated donor and received GVHD prophylaxis for 180 days. Filgrastim was administered post HCT until neutrophil recovery. Infections were graded according to Cordonnier et al. (Transplantation 2006). Only proven/probable pulmonary fungal episodes by EORT/MSG criteria were included. Infection prophylaxis during the study period included trimethoprim/sulfamethoxazole BID thrice weekly after HCT engraftment and daily acyclovir or valacyclovir. Fungal prophylaxis was fluconazole until day 100 or either micafungin or voriconazole in persons receiving 1+ week of >1 mg/kg/d prednisone or equivalent. Ceftazidime was administered to persons with neutrophil count <500/μL until recovery. Persons were monitored for CMV, adenovirus, toxoplasmosis (in seropositive persons), EBV (after 2009), and HHV-6 with at least weekly blood PCR. CMV was treated with pre-emptive therapy according to published guidelines. Blood aspergillus glactomannin and beta D-glucan assays were obtained when clinically indicated. The use of AC compared to TMS resulted in greater total infections per patient (4.4 versus 2.8, P<0.0001) but similar rates of grade 3 (most serious) infections (0.5 versus 0.6, P=0.49). CMV reactivation in recipient seropositive persons was more common in AC (24/24 AC arm versus 11/24 TMS arm, P<0.0001). The median duration of CMV viremia was 6 weeks in AC versus 2 weeks in TMS (P=0.001). CMV colitis or pneumonitis occurred in 3 persons treated with AC and in 1 person treated with TMS at a mean of 47 days post alloHCT (range 15-121). Bacterial infections per patient in AC and TMS were similar (1.6 versus 1.1, P=0.08). Clostridium difficile colitis was relatively common (10 episodes AC; 11 episodes TMS). HHV-6 infections were similar (24/40 AC versus 16/38 TMS, P=0.16). HHV-6 encephalitis developed in five individuals (3 TMS, 2 AC). The median blood titer at the time CNS involvement was identified was 15,950 copies/mL (0-40,000 copies/mL) and was not predictive on onset of encephalopathy (P=0.6). EBV infection developed in 9 persons in AC and 6 persons in TMS. Three cases of EBV lymphoproliferative disorder occurred in persons treated with AC. An additional three persons in each AC and TMS were treated pre-emptively with rituximab for EBV viremia. Adenovirus infection developed in 4 persons in each TMS and AC. One person treated with AC developed adenoviral colitis. There was one episode of invasive fungal infection in TMS (Candida krusei blood stream infection) and 4 episodes in AC (3 episodes Candida blood stream infection [2 parapsilosis, 1 albicans], one pulmonary aspergillosis). In summary, the use of AC versus TMS resulted greater total infections and CMV infections but with similar bacterial and fungal infection incidence. Weekly monitoring of HHV-6 by blood PCR was ineffective at predicting development of HHV-6 CNS disease. The rate of invasive fungal infections in this cohort was low. Disclosures: No relevant conflicts of interest to declare.
-
host Lymphocyte Depletion as a strategy to facilitate early full donor chimerism after reduced intensity allogeneic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2013Co-Authors: Rachel B Salit, Ronald E Gress, Seth M Steinberg, Robert M Dean, Steven Z Pavletic, Daniel H Fowler, Frances T Hakim, Nancy T Hardy, Claude Sportes, Michael R BishopAbstract:Abstract Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host Lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted Lymphocyte Depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and Lymphocyte Depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating Lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4+ count. All patients engrafted; there were no late graft failures. By day +14, median CD3+ chimerism was 99% donor and was significantly associated with lower post-TLD CD4+ counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.
-
use of targeted Lymphocyte Depletion as a personalized approach to improve engraftment and disease control following reduced intensity allogeneic hematopoietic stem cell transplantation using hla matched unrelated donors
Blood, 2010Co-Authors: Rachel B Salit, Seth M Steinberg, Steven Z Pavletic, Daniel H Fowler, Frances T Hakim, Kelly Bryant, Jennifer Wilder, Michael R BishopAbstract:Abstract Abstract 3530 Reduced-intensity allogeneic stem cell transplantation (RIST) using unrelated donors (URD) is associated with delayed full donor chimerism, higher rejection rates, and increased risk of graft versus host disease (GVHD) compared to RIST with HLA-matched sibling donors. We have previously reported a strategy of targeted Lymphocyte Depletion (TLD) to facilitate early full-donor chimerism in patients receiving RIST from HLA-matched siblings. TLD attempts to compensate for variability in host immune status, using CD4+ T-Lymphocytes as a surrogate marker, by giving repetitive cycles of disease-specific conventional-dose chemotherapy to deplete host Lymphocytes and provide tumor cytoreduction prior to RIST. We initiated a prospective pilot trial of TLD in the setting of RIST from 10/10 HLA-matched URD. TLD was achieved by using disease-specific induction chemotherapy (EPOCH-F/R or FLAG) for 0–3 cycles to reach a target Lymphocyte count of Disclosures: No relevant conflicts of interest to declare.
-
targeted Lymphocyte Depletion prior to reduced intensity allogeneic stem cell transplantation a personalized approach to facilitate engraftment
Blood, 2009Co-Authors: Rachel B Salit, Seth M Steinberg, Daniel H Fowler, Jeanne Odom, Kelly Bryant, Michael R BishopAbstract:Abstract 865 Reduced intensity allogeneic stem cell transplantation (RIST) is associated with decreased transplant-related mortality (TRM), broadening the pool of patients who could potentially benefit from allogeneic cellular therapy. However, RIST is typically associated with higher rates of mixed chimerism and graft rejection compared to myeloablative conditioning. Data from clinical studies have shown that the number of therapies prior to transplant, which inversely correlates with host T-cell immunity, is a statistically important predictor of graft rejection and mixed chimerism. In order to compensate for variability in host immune status and facilitate early full-donor chimerism (>95%), we developed a strategy of targeted Lymphocyte Depletion (TLD) which uses repetitive cycles of disease-specific conventional-dose chemotherapy to provide both tumor cytoreduction and Lymphocyte Depletion prior to RIST. The number of TLD cycles (0-3 maximum) was based on reaching a target CD4 + count + count required more cycles. We employed the TLD approach in 111 patients (mean age = 49 years, (19-71) with advanced hematologic malignancies. Median CD3 + , CD4 + , and CD8 + counts at enrollment were: 673 cells/μl (5-3953), 286 cells/μl (5-3888), and 277 cells/μl (1-1763) respectively. Following TLD chemotherapy, median CD3 + , CD4 + , and CD8 + counts were: 164 cells/μl (1-1496), 82 cells/μl (0-508), and 52 cells/μl (1-1195) respectively. All patients then received an identical reduced intensity conditioning regimen (fludarabine/cyclophosphamide) followed by HLA-matched sibling peripheral blood stem cell allografts. All patients received cyclosporine as graft versus host disease (GVHD) prophylaxis (1) alone, (2) with methotrexate, (3) with TH2 cells, (4) with sirolimus or (5) with TH2 cells and sirolimus. Immediately prior to stem cell infusion (Day 0) median host CD3 + , CD4 +, and CD8+ counts were 4 cells/μl (0-69), 3 cells/μl (0-65) , and 1 cell/μl (0-44) respectively. 109 evaluable patients demonstrated 100% engraftment; there were no graft failures. At Day +14, median Lymphocyte chimerism was 99% and median myeloid and whole blood chimerism were 100%. Patients were able to maintain chimerism as evidenced by median 100% chimerism in the myeloid, lymphoid and whole blood compartments at Day +28 and median 100% whole blood chimerism at Day +100. Full donor Lymphocyte chimerism at Day +14 was associated with lower post-TLD CD4 + counts (p=0.012) and Day 0 CD3 + , CD4 + , and CD8 + counts (p + , CD4 + , CD8 + counts (p + , CD4 + , and CD8 + counts (p + counts post-TLD (p=0.01). Patients with acute GVHD III-IV had significantly lower CD4 + and CD3 + counts at Day 0 (p Disclosures: No relevant conflicts of interest to declare.
-
targeted Lymphocyte Depletion a personalized approach to achieve rapid complete donor chimerism and enhance graft versus tumor effects following reduced intensity allogeneic stem cell transplantation for high risk hematologic malignancies
Blood, 2009Co-Authors: Rachel B Salit, Seth M Steinberg, Daniel H Fowler, Jeanne Odom, Kelly Bryant, Michael R BishopAbstract:Abstract 656 Reduced intensity allogeneic stem cell transplantation (RIST) is associated with decreased transplant-related mortality (TRM), broadening the pool of patients who could potentially benefit from allogeneic cellular therapy. However, RIST historically results in mixed chimerism, has higher relapse rates and has limited efficacy in chemotherapy-refractory hematologic malignancies. In order to enhance graft-versus-tumor effects, we have developed a strategy of targeted Lymphocyte Depletion (TLD), which attempts to compensate for variability in host immune status and facilitate early full-donor chimerism. TLD involves the use of repetitive cycles of disease-specific conventional-dose chemotherapy to provide both tumor cytoreduction and Lymphocyte Depletion prior to RIST. The number of TLD cycles (0-3 maximum) is based on reaching a target CD4 + count + counts require more cycles. We employed the TLD approach in 111 patients (40 females/71 males) with median age of 50 years (range 19-71) with advanced hematologic malignancies (45% chemotherapy refractory; 60% high risk of relapse by Seattle Criteria (Kahl C et al Blood 2007). Median CD3 + , CD4 + , and CD8 + counts at enrollment were 673 cells/μl (5-3953), 286 cells/μl (5-3888), and 277 cells/μl (1-1763) respectively. Following TLD chemotherapy, median CD3 + ,CD4 + , and CD8 + counts were 164 cells/μl (1-1496), 82 cells/μl (0-508) and 52 cells/μl (1-1195) respectively. All patients then received an identical reduced intensity conditioning regimen (fludarabine/cyclophosphamide) followed by T-cell replete HLA-matched sibling peripheral blood stem cell allografts and cyclosporine-based graft versus host disease (GVHD) prophylaxis. 109 evaluable patients demonstrated 100% engraftment; there were no late graft failures. At Day+14, median Lymphocyte chimerism was 99% and median myeloid and whole blood chimerism were 100%. Patients were able to maintain chimerism as evidenced by 100% median chimerism in the myeloid, lymphoid and whole blood compartments at Day+28 and 100% median whole blood chimerism at Day +100. The cumulative incidence of grades II-IV and grades III-IV acute GVHD was 46% and 23% respectively. The cumulative incidence of chronic GVHD was 59% (15% limited, 44% extensive). One and 5-year TRM was 15% and 21% respectively. At Day +28, 38 patients had achieved a complete remission (CR) and 44 achieved partial remission (PR). Twelve additional CRs were observed at Day +100 without withdrawal of immunosuppression or donor Lymphocyte infusion. Event free survival (EFS) and overall survival (OS) at one year were 49% and 66% respectively. EFS and OS at five years were 31% and 47% respectively. Of those patients alive at one year (n=73), 66% were in CR. Of those patients in CR, 58% had high risk of relapse by Seattle Criteria and 92% had not been in CR at the time of transplant (31% had stable or progressive disease). At median follow-up of 5.4 years, 65% of this subset of patients were alive and still in CR. By univariate analysis, the age of the recipient and presence of an ABO minor mismatch were significantly associated with OS (p Disclosures: No relevant conflicts of interest to declare.
M J Leandro - One of the best experts on this subject based on the ideXlab platform.
-
repeated b Lymphocyte Depletion with rituximab in rheumatoid arthritis over 7 yrs
Rheumatology, 2006Co-Authors: C Popa, M J Leandro, G Cambridge, Jcw EdwardsAbstract:Objective To assess safety and efficacy of repeated B-cell Depletion with rituximab in patients with rheumatoid arthritis (RA). Methods Thirty-seven patients with refractory RA entered into a programme of repeated B-Lymphocyte Depletion (up to 5 cycles, 89 cycles in total) with protocols based on the anti-CD20 monoclonal antibody, rituximab, have been observed over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Results Twenty two subjects have been followed up for >5 yrs. Average duration of benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximab +/- cyclophosphamide (cy) carcinomata have developed as follows: breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunoglobulin levels to below the normal range occurred in 12 patients for IgM (undetectable levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunoglobulin levels before the first cycle. Conclusion Repeated B-Lymphocyte Depletion over a 5-yr period appears to be an acceptable and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunoglobulin levels require surveillance.
-
b Lymphocyte Depletion in rheumatoid arthritis targeting of cd20
Current directions in autoimmunity, 2005Co-Authors: Jonathan C W Edwards, M J Leandro, G CambridgeAbstract:Background: During the 1990s evidence emerged to suggest that B Lymphocyte Depletion in rheumatoid arthritis (RA) might be of major benefit. Methods and Results: In 1997 the B lympholytic monoclonal
-
b Lymphocyte Depletion therapy with rituximab in rheumatoid arthritis
Rheumatic Diseases Clinics of North America, 2004Co-Authors: Jcw Edwards, M J Leandro, G CambridgeAbstract:B Lymphocyte Depletion therapy in rheumatoid arthritis can provide major clinical benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. Rituximab is a highly effective agent, but it may be best used in combination with other agents. Substantial improvement following a single course of therapy has been found to last up to 42 months, and it is reasonable to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.
-
serologic changes following b Lymphocyte Depletion therapy for rheumatoid arthritis
Arthritis & Rheumatism, 2003Co-Authors: G Cambridge, Jonathan C W Edwards, M J Leandro, Michael R Ehrenstein, Martin Salden, M D Bodmansmith, Anthony D B WebsterAbstract:Objective To explore the changes in serologic variables and clinical disease activity following B Lymphocyte Depletion in 22 patients with rheumatoid arthritis (RA). Methods B Lymphocyte Depletion was attained using combination therapy based on the monoclonal anti-CD20 antibody rituximab. Levels of a serologic indicator of inflammation, C-reactive protein (CRP), of antimicrobial antibodies, of autoantibodies including IgA-, IgM-, and IgG-class rheumatoid factors (RF), and of antibodies to cyclic citrullinated peptide (anti-CCP) were assayed. Results The majority of patients showed a marked clinical improvement after treatment with rituximab, with benefit lasting up to 33 months. Levels of total serum immunoglobulins fell, although the mean values each remained within the normal range. Whereas the IgM-RF response paralleled the changes in total serum IgM levels, the levels of IgA-RF, IgG-RF, and IgG and anti-CCP antibodies decreased significantly more than did those of their corresponding total serum immunoglobulin classes. The kinetics for the reduction in CRP levels also paralleled the decreases in autoantibody levels. In contrast, levels of antimicrobial antibodies did not change significantly. B Lymphocyte return occurred up to 21 months posttreatment. The time to relapse after B Lymphocyte return was often long and unpredictable (range 0–17 months). Relapse was, however, closely correlated with rises in the level of at least one autoantibody. Increased autoantibody levels were rarely observed in the absence of clinical change. Conclusion Following B Lymphocyte Depletion in patients with RA, a positive clinical response occurred in correlation with a significant drop in the levels of CRP and autoantibodies. Antibacterial antibody levels were relatively well maintained. B Lymphocyte return preceded relapse in all patients. There was also a temporal relationship between clinical relapse and rises in autoantibody levels. Although these observations are consistent with a role for B Lymphocytes in the pathogenesis of RA, the precise mechanisms involved remain unclear.
-
an open study of b Lymphocyte Depletion in systemic lupus erythematosus
Arthritis & Rheumatism, 2002Co-Authors: M J Leandro, G Cambridge, Jonatha C W Edwards, Michael R Ehrenstei, David A IsenbergAbstract:Objective To gain preliminary evidence for the safety and efficacy of B Lymphocyte Depletion therapy in refractory systemic lupus erythematosus (SLE). Methods Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-label basis. During a 2-week period, each patient received two 500-mg infusions of rituximab, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids. Results No significant adverse events were observed during followup. Patient 1 had not improved at 3 months but was then lost to followup. At 6 months, all 5 remaining patients had improved, as evidenced by improvement in British Isles Lupus Assessment Group global scores, from a median of 14 (range 9–27) at baseline to a median of 6 (range 3–8) at 6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. Hemoglobulin levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation rate decreased in patients 2, 3, 4, and 5 and was stable in patient 1. In patients 4 and 5, the urinary protein–to-creatinine ratio decreased significantly. C3 serum levels increased in all 5 patients who had low levels at baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. The variation in the level of anti–double-stranded DNA antibody was different in individual patients. Conclusion This study provides sufficient evidence for the safety and possible efficacy of B Lymphocyte Depletion therapy in SLE to justify a formal controlled trial.
Alasdair Coles - One of the best experts on this subject based on the ideXlab platform.
-
il 21 drives secondary autoimmunity in patients with multiple sclerosis following therapeutic Lymphocyte Depletion with alemtuzumab campath 1h
Journal of Clinical Investigation, 2009Co-Authors: Joanne L. Jones, Chialing Phuah, Sara A Thompson, Jacqueline Shawcross, Amie Walton, Stephen Sawcer, Alastair Compston, Alasdair ColesAbstract:Phase II clinical trials revealed that the Lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced Lymphocyte Depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering Lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
-
Lymphocyte homeostasis following therapeutic Lymphocyte Depletion in multiple sclerosis
European Journal of Immunology, 2005Co-Authors: Amanda L Cox, Sara A Thompson, Joanne L. Jones, Vicki Robertson, Geoff Hale, Herman Waldmann, Alastair D S Compston, Alasdair ColesAbstract:Following Lymphocyte Depletion, homeostatic mechanisms drive the reconstitution of Lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath-1H, a humanised anti-CD52 monoclonal antibody. We observed two phases of Lymphocyte reconstitution. In the first 6 months after treatment the precursor frequency and proliferation index of the patients' autologous mixed Lymphocyte reaction increased; the depleted T cell pool was dominated by memory T cells, especially (CD4+)CD25high T cells, a putative regulatory phenotype; and there was a non-significant rise in peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive cytokine mRNA expression. In the later phase, from 6-to-12 months after Campath-1H, these changes reversed and there was a rise in ROG mRNA expression. However, total CD4+ numbers remained below 50% of pre-treatment levels at 12 months, perhaps reflecting a failure in homeostasis. This was not due to an impaired IL-7 response, as in rheumatoid arthritis, nor to a lack of IL-7 receptors, which are found on fewer human (CD4+)CD25high than naive cells. We speculate that CCL21 and IL-15 responses to lymphopaenia may be suboptimal in multiple sclerosis.
Ronald E Gress - One of the best experts on this subject based on the ideXlab platform.
-
infectious complications after unrelated donor allogeneic hematopoietic cell transplantation with or without alemtuzumab based in vivo Lymphocyte Depletion
Blood, 2013Co-Authors: Andrew Flynn, Ronald E Gress, Michael R Bishop, Juan Geabanacloche, Rachel B Salit, Frances T Hakim, David Moorshead, Zach Powell, Jennifer Hsu, Steven Z PavleticAbstract:The addition of alemtuzumab to conditioning may decrease the incidence of graft versus host disease (GVHD) after unrelated donor (URD) allogeneic hematopoietic cell transplantation (alloHCT) but may also contribute to impaired pathogen immunity due to donor Lymphocyte Depletion. We identified and graded infections occurring within 6 months after URD alloHCT in 78 individuals treated either with (N=40) or without (N=38) alemtuzumab during alloHCT for hematologic cancers. Conditioning included fludarabine (120 mg/m2 total) and cyclophosphamide (4,800 mg/m2 total) over 4 days with either alemtuzumab (100 mg total days -8 to -4) followed by cyclosporine (AC) or with tacrolimus, methotrexate, and sirolimus (TMS) based GVHD prophylaxis. Both groups received a filgrastim mobilized peripheral blood graft from an 8/8 or 7/8 HLA-matched unrelated donor and received GVHD prophylaxis for 180 days. Filgrastim was administered post HCT until neutrophil recovery. Infections were graded according to Cordonnier et al. (Transplantation 2006). Only proven/probable pulmonary fungal episodes by EORT/MSG criteria were included. Infection prophylaxis during the study period included trimethoprim/sulfamethoxazole BID thrice weekly after HCT engraftment and daily acyclovir or valacyclovir. Fungal prophylaxis was fluconazole until day 100 or either micafungin or voriconazole in persons receiving 1+ week of >1 mg/kg/d prednisone or equivalent. Ceftazidime was administered to persons with neutrophil count <500/μL until recovery. Persons were monitored for CMV, adenovirus, toxoplasmosis (in seropositive persons), EBV (after 2009), and HHV-6 with at least weekly blood PCR. CMV was treated with pre-emptive therapy according to published guidelines. Blood aspergillus glactomannin and beta D-glucan assays were obtained when clinically indicated. The use of AC compared to TMS resulted in greater total infections per patient (4.4 versus 2.8, P<0.0001) but similar rates of grade 3 (most serious) infections (0.5 versus 0.6, P=0.49). CMV reactivation in recipient seropositive persons was more common in AC (24/24 AC arm versus 11/24 TMS arm, P<0.0001). The median duration of CMV viremia was 6 weeks in AC versus 2 weeks in TMS (P=0.001). CMV colitis or pneumonitis occurred in 3 persons treated with AC and in 1 person treated with TMS at a mean of 47 days post alloHCT (range 15-121). Bacterial infections per patient in AC and TMS were similar (1.6 versus 1.1, P=0.08). Clostridium difficile colitis was relatively common (10 episodes AC; 11 episodes TMS). HHV-6 infections were similar (24/40 AC versus 16/38 TMS, P=0.16). HHV-6 encephalitis developed in five individuals (3 TMS, 2 AC). The median blood titer at the time CNS involvement was identified was 15,950 copies/mL (0-40,000 copies/mL) and was not predictive on onset of encephalopathy (P=0.6). EBV infection developed in 9 persons in AC and 6 persons in TMS. Three cases of EBV lymphoproliferative disorder occurred in persons treated with AC. An additional three persons in each AC and TMS were treated pre-emptively with rituximab for EBV viremia. Adenovirus infection developed in 4 persons in each TMS and AC. One person treated with AC developed adenoviral colitis. There was one episode of invasive fungal infection in TMS (Candida krusei blood stream infection) and 4 episodes in AC (3 episodes Candida blood stream infection [2 parapsilosis, 1 albicans], one pulmonary aspergillosis). In summary, the use of AC versus TMS resulted greater total infections and CMV infections but with similar bacterial and fungal infection incidence. Weekly monitoring of HHV-6 by blood PCR was ineffective at predicting development of HHV-6 CNS disease. The rate of invasive fungal infections in this cohort was low. Disclosures: No relevant conflicts of interest to declare.
-
host Lymphocyte Depletion as a strategy to facilitate early full donor chimerism after reduced intensity allogeneic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2013Co-Authors: Rachel B Salit, Ronald E Gress, Seth M Steinberg, Robert M Dean, Steven Z Pavletic, Daniel H Fowler, Frances T Hakim, Nancy T Hardy, Claude Sportes, Michael R BishopAbstract:Abstract Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host Lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted Lymphocyte Depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and Lymphocyte Depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating Lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4+ count. All patients engrafted; there were no late graft failures. By day +14, median CD3+ chimerism was 99% donor and was significantly associated with lower post-TLD CD4+ counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.
-
reconstitution of the Lymphocyte compartment after Lymphocyte Depletion a key issue in clinical immunology
European Journal of Immunology, 2005Co-Authors: Frances T Hakim, Ronald E GressAbstract:Loss of existing T cell populations is a significant clinical problem following cytoreductive therapies or in disease states such as HIV. Characterization of the pathways of T cell regeneration, their limitations and regulation, is central to the development of new approaches for the correction of T cell lymphopenia. Recently, there has been an increasing appreciation that subsets of T cells differ not only in requirements for homeostasis, but in the mechanisms of initial generation and later reconstitution of lost populations. In this issue, Cox et al. determine that variations in cytokine/chemokine levels may affect the biology of T cell recovery which impacts on the development of treatment strategies for lymphopenia. See accompanying article: http://dx.doi.org/10.1002/eji.200535075
-
targeted pretransplant host Lymphocyte Depletion prior to t cell depleted reduced intensity allogeneic stem cell transplantation
British Journal of Haematology, 2004Co-Authors: Michael R Bishop, Ronald E Gress, Seth M Steinberg, Nancy M Hardy, Donna Marchigiani, Claude Kastensportes, Robert M Dean, Steven Z Pavletic, Juan Geabanacloche, Kathleen CastroAbstract:SummaryMixed chimaerism and graft rejection are higher after reduced-intensityallogeneic stem cell transplantation (RIST) with T-cell depleted (TCD)allografts. As host immune status before RIST affects engraftment, wehypothesized that targeted Depletion of host Lymphocytes prior to RISTwould abrogate graft rejection and promote donor chimaerism. Lymphocyte-depleting chemotherapy was administered at conventional doses to subjectsprior to RIST with the intent of decreasing CD4 + counts to <0AE05 · 10 9 cells/l. Subjects (n ¼ 18) then received reduced-intensity conditioningfollowed by ex vivo TCD human leucocyte antigen-matched siblingallografts. All evaluable patients (n ¼ 17) were engrafted; there were nolate graft failures. At day +28 post-RIST, 12 patients showed complete donorchimaerism. Mixed chimaerism in the remaining five patients was associatedwith higher numbers of circulating host CD3 + cells (P ¼ 0AE0032) afterLymphocyte-depleting chemotherapy and was preferentially observed in Tlymphoid rather than myeloid cells. Full donor chimaerism was achieved inall patients after planned donor Lymphocyte infusions. These data reflect theimportance of host immune status prior to RIST and suggest that targetedhost Lymphocyte Depletion facilitates the engraftment of TCD allografts.Targeted Lymphocyte Depletion may permit an individualized approach toconditioning based on host immune status prior to RIST.Keywords: allogeneic, T-cell Depletion, reduced-intensity, graft rejection.
-
demodicidosis in childhood acute lymphoblastic leukemia an opportunistic infection occurring with immunosuppression
The Journal of Pediatrics, 1995Co-Authors: Percy S Ivy, Crystal L Mackall, Lia Gore, Ronald E Gress, Howland A HartleyAbstract:Abstract We report demodicidosis in 11 children with acute lymphoblastic leukemia and a mildly pruritic, erythematous papular dermatitis that developed in areas rich in sebaceous glands. Demodex eruptions were safely and effectively treated with 5% permethrin. Proliferation of commensal parasites of the skin, Demodex folliculorum and Demodex brevis may be an opportunistic infection of the skin in the immunocompromised host; the expected abrogation of cell-mediated immunity secondary to Lymphocyte Depletion predisposes some children given chemotherapy for leukemia to mite proliferation. (J P EDIATR 1995;127:751-4)
