Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Norihiro Nishimoto ◽  
Mitsuko Sasai ◽  
Yoshihito Shima ◽  
Masashi Nakagawa ◽  
Tomoshige Matsumoto ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Plasma Cell ◽  
Interleukin 6 ◽  
Castleman’S Disease ◽  
Serum Levels ◽  
Secondary Amyloidosis ◽  
Castleman's Disease ◽  
Follicular Hyperplasia ◽  
Receptor Antibody ◽  
Systemic Manifestations

Abstract Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease. (Blood. 2000;95:56-61)

Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Norihiro Nishimoto ◽  
Mitsuko Sasai ◽  
Yoshihito Shima ◽  
Masashi Nakagawa ◽  
Tomoshige Matsumoto ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Plasma Cell ◽  
Interleukin 6 ◽  
Castleman’S Disease ◽  
Serum Levels ◽  
Secondary Amyloidosis ◽  
Castleman's Disease ◽  
Follicular Hyperplasia ◽  
Receptor Antibody ◽  
Systemic Manifestations

Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease. (Blood. 2000;95:56-61)

scholarly journals Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1360-1367 ◽  
Author(s):  
K Yoshizaki ◽  
T Matsuda ◽  
N Nishimoto ◽  
T Kuritani ◽  
L Taeho ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Proteins ◽  
Castleman’S Disease ◽  
Germinal Centers ◽  
Surgical Removal ◽  
Castleman's Disease ◽  
Lymph Node Hyperplasia

Abstract Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.

ANTI-INTERLEUKIN 6 (IL-6) RECEPTOR ANTIBODY SUPPRESSES CASTLEMAN'S DISEASE LIKE SYMPTOMS EMERGED IN IL-6 TRANSGENIC MICE

Cytokine ◽  
2002 ◽  
Vol 20 (6) ◽  
pp. 304-311 ◽  
Author(s):  
Asao Katsume ◽  
Hiroyuki Saito ◽  
Yoshiki Yamada ◽  
Keigo Yorozu ◽  
Otoya Ueda ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Interleukin 6 ◽  
Castleman’S Disease ◽  
Castleman's Disease ◽  
Receptor Antibody

Monitoring of Serum Hepcidin-25 in Multicentric Castleman’s Disease Patients Treated with Tocilizumab, an Anti-Interleukin-6 Receptor Antibody.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3686-3686
Author(s):  
Hiroshi Kawabata ◽  
Naohisa Tomosugi ◽  
Junya Kanda ◽  
Chisaki Mizumoto ◽  
Yasuhiro Tanaka ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Interleukin 6 ◽  
Castleman’S Disease ◽  
Microcytic Anemia ◽  
Castleman's Disease ◽  
Multicentric Castleman’S Disease ◽  
Hepcidin Level ◽  
Receptor Antibody ◽  
Serum Hepcidin ◽  
Multicentric Castleman's Disease

Abstract Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder with systemic manifestations such as lymphadenopathy, fever and microcytic anemia. Over-production of interleukin-6 (IL-6) has been speculated to be a key event in the pathogenesis of this disorder. IL-6 is known to stimulate hepatic expression of hepcidin, a central regulator of body iron homeostasis. We developed a SELDI-TOF mass spectrometry-based semi-quantitative method for serum hepcidin-25 (Tomosugi N, et al. Blood108, 1381–7, 2006). Utilizing this method, we previously reported a rapid decrease in serum hepcidin-25 in two MCD patients after administration of tocilizumab, an anti-IL-6 receptor antibody (Kawabata H, et al. Haematologica92, 857–8, 2007). Recently, by introducing liquid chromatography tandem mass-spectrometry and an isotopic hepcidin as an internal standard, we developed another serum hepcidin quantification system with very small intra- and inter-assay CVs. Utilizing this new method in this study, we further evaluated the clinical relevance of monitoring serum hepcidin in MCD patients treated with tocilizumab. Serum hepcidin-25 was monitored in 5 MCD cases including two previously reported cases (Cases 1 and 2). Tocilizumab (8 mg/kg body weight) was administered intravenously at 2-week intervals. This study was approved by the Ethics Committee of Kyoto University Graduate School and the Faculty of Medicine. Written informed consent was obtained from each patient. The initial levels of serum hepcidin-25 before tocilizumab treatment varied widely, between 14 and 256 ng/ml (normal range, 22 ± 12 ng/ml). In all cases, rapid reduction of serum hepcidin-25 was observed after the initial dose of tocilizumab, followed by decreases of C-reactive protein and gradual improvement of anemia (Table 1). In Case 5, the initial hepcidin level was extremely high (256 ng/ml) and it decreased only slightly after tocilizumab administration. In this case, the serum hepcidin level on day 35 remained considerably elevated (90.5 ng/ml) even after 3 doses of tocilizumab. On the same day, an anti-tocilizumab antibody was detected in the serum, and this medication was discontinued. In the other 4 cases, serum hepcidin levels decreased below the upper normal limit within 2 weeks. After 16 weeks treatment with tocilizumab, Hb increased from 5.7 to 11.2 g/dl in Case 1, from 10.2 to 11.9 g/dl in Case 2, from 6.3 to 11.0 g/dl in Case 3 and from 8.2 to 13.7 g/dl in Case 4. There were no apparent side effects in these 4 cases. These findings imply that inadequate levels of serum hepcidin caused by overproduction of IL-6 are associated with the pathogenesis of microcytic anemia observed in MCD patients. Monitoring of serum hepcidin may be useful to evaluate the efficacy of tocilizumab in MCD cases. Table 1 Case 1 Case 2 Case 3 Case 4 Case 5 Pre/Day14 Pre/Day14 Pre/Day14 Pre/Day14 Pre/Day14 Hepcidin-25 (ng/ml) 44.8/2.2 55.5/24.6 14/0.8 43.5/1.5 256/166 CRP (mg/dl) 24.3/5.4 11.7/4.1 16.9/3.6 7.6/0.2 11.9/6.8 Hb (g/dl) 5.7/9.2 10.2/11.2 6.3/7.9 8.2/9.4 6.5/7.4

scholarly journals Interleukin-6 gene expression in Castleman's disease

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2923-2930 ◽  
Author(s):  
MB Leger-Ravet ◽  
M Peuchmaur ◽  
O Devergne ◽  
J Audouin ◽  
M Raphael ◽  
...  
Keyword(s):  
Gene Expression ◽  
In Situ Hybridization ◽  
Lymph Nodes ◽  
Interleukin 6 ◽  
Plasma Cells ◽  
Castleman’S Disease ◽  
Systemic Manifestations ◽  
Gene Expressing ◽  
Localized Form

Abstract Defined by histological criteria, Castleman's disease (CD) is a clinically and histologically heterogeneous syndrome. The functional status of immune cells in affected tissues may vary between the different forms of the disease. To address this question, the expression of cytokine genes in eight CD lymph nodes was analyzed by in situ hybridization. Two lymph nodes were taken from patients with a localized form of the disease associated with systemic manifestations, two from patients with a localized form without systemic symptoms, and four from patients with a multicentric form. Five lymph nodes exhibiting a benign follicular hyperplasia were used as controls. The interleukin-6 (IL-6) gene was expressed at a very high level in two cases: the two localized forms of CD associated with systemic manifestations. IL-6 gene overexpression occurred inside follicles of these lymph nodes. The morphology of follicular cells hybridizing with the IL-6 probe or labeled with an anti-IL-6 monoclonal antibody suggested that follicular dendritic cells expressed the IL-6 gene. In contrast, no IL-6 gene expression was detected inside follicles of the six other CD lymph nodes or of the five control lymph nodes. In interfollicular areas, IL-6 gene-expressing cells were detected in all lymph nodes by both in situ hybridization and immunohistochemistry. In CD lymph nodes, positive cells were located outside sinuses, in close contact with blood vessels and plasma cells. This distribution was clearly different from that observed in control lymph nodes, in which IL-6 gene-expressing cells were present inside sinuses. A similar difference between CD and control lymph nodes was observed for the distribution of IL-1 beta and IL-1 alpha gene-expressing cells in interfollicular areas. The morphology of interfollicular IL-6-producing cells was heterogeneous, consistent with that of macrophages, interdigitating cells, lymphocytes, and endothelial cells, and different from that of plasma cells. Taken together these results show that CD is consistently associated with a particular pattern of IL-6 gene expression in interfollicular areas whereas elevated IL-6 gene expression inside follicles only occurs in the localized form of the disease associated with systemic manifestations. The variable pattern of IL-6 gene expression as well as the clinical and histologic heterogeneity of CD indicate that different immune mechanisms may be involved in the different forms of this disease.

scholarly journals Effectiveness of Humanized Anti-interleukin-6 Receptor Antibody (tocilizumab) for Castleman's Disease Mainly with Pulmonary Involvement

2007 ◽  
Vol 96 (5) ◽  
pp. 988-990 ◽  
Author(s):  
Nobuhito Ohno ◽  
Sayuri Fujiyama ◽  
Masaomi Ooi ◽  
Kouichi Haraguchi ◽  
Masahito Tokunaga ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Castleman’S Disease ◽  
Pulmonary Involvement ◽  
Castleman's Disease ◽  
Receptor Antibody ◽  
Interleukin 6 Receptor

scholarly journals Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1360-1367 ◽  
Author(s):  
K Yoshizaki ◽  
T Matsuda ◽  
N Nishimoto ◽  
T Kuritani ◽  
L Taeho ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Proteins ◽  
Castleman’S Disease ◽  
Germinal Centers ◽  
Surgical Removal ◽  
Castleman's Disease ◽  
Lymph Node Hyperplasia

Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.

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