Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma

To compare V kappa gene usage and the amount of somatic mutation in rearranged Ig genes from patients with lymphoproliferative disorders, we have polymerase chain reaction-amplified and sequenced a total of 26 V kappa genes from a total of 55 cases. Six sequences were obtained both from six cases of prolymphocytic leukemia (PLL) and from nine cases of hairy cell leukemia (HCL). Seven sequences were obtained both from 11 cases of Waldenstrom's macroglobulinemia (WM) and 29 cases of multiple myeloma (MM). Eleven different germline genes have been used in this series, indicating a wide but nonrandom usage of germline Ig gene rearrangements in these disorders. Comparison of the nucleotide sequences of V kappa genes obtained from B-cell malignancies with germline V kappa genes shows that somatic mutation is rare in PLL and HCL and common in WM and MM. Analysis of the pattern of mutations suggests that WM and MM are derived from B cells that have been selected by antigen at a relatively late stage of differentiation.     

IgM multiple myeloma: Disease definition,prognosis, and differentiation from Waldenstrom's macroglobulinemia

IgM multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty‐one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non‐IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Recombinant alpha-2 interferon in the treatment of hairy cell leukemia

We treated 14 patients with hairy cell leukemia, 13 of whom had progressive disease, with recombinant alpha-2 interferon administered sc at 2 X 10(6) units/m2, three times per week. Thirteen patients were evaluable for response. All evaluable patients responded within 6-8 weeks. After a minimal treatment duration of 6 months and a maximal of 12 months, three patients have achieved complete response and ten have achieved partial response. With a median treatment duration of 10 months, the responding patients' hematologic parameters are continuing to improve, and no responding patients have relapsed. This outpatient self-administered regimen is well-tolerated, with mild fever, myalgias, and headache usually resolving within 2 months. Although the optimal regimen and the mechanism of action are unknown, recombinant alpha-2 interferon may be the treatment of choice for patients whose disease progresses after splenectomy or who are not surgical candidates.     

Effect of interferon alpha-2b in advanced multiple myeloma

The antitumour effect of recombinant human interferon (rh-IFN) alpha-2b was studied in 22 patients with advanced multiple myeloma (MM). Nine of 14 evaluable cases were refractory to cytostatic therapy; five were in relapse. rh-IFN was administered s.c. three times per week, in escalating doses starting with 2 x 10(6) IU m-2 and if possible up to 15 x 10(6) IU m-2. Two patients (one refractory, one relapsing) showed a partial response, defined as a 50% reduction of the serum M-component. Three further patients had a minor, significant but short-lived response. Subjective side-effects grade 1-2 were noted during rh-IFN therapy in all patients. In three cases thrombocytopenia necessitating platelet transfusions occurred. Although a fraction of patients with advanced MM obviously respond to rh-IFN, this type of therapy may be more effective, alone or in addition to chemotherapy, in patients with a low tumour cell burden.     

Recombinant alpha-2 interferon for treatment of hairy cell leukemia without prior splenectomy

Splenectomy has been the traditional initial treatment for hairy cell leukemia, with medical treatment reserved for resistant disease. This report describes two patients treated with recombinant alpha-2 interferon without prior splenectomy. Both patients responded well to interferon therapy. Alpha-2 interferon may become the initial therapy of choice for hairy cell leukemia.     

Splenectomy vs. alpha interferon: a randomized study in patients with previously untreated hairy cell leukemia.

Twenty patients with previously untreated hairy cell leukemia were randomized to undergo either splenectomy or to receive interferon alfa-N1, a highly purified natural alpha interferon, as primary therapy. A response in the peripheral blood elements to a hemoglobin greater than 110 gm/l, a granulocyte count greater than 1 x 10(9)/l, and a platelet count greater than 100 x 10(9)/l (Catovsky criteria) was noted in all ten patients receiving alpha interferon but in only three of the patients undergoing splenectomy (P = less than .01). Median time to response was longer in the ten interferon patients (153 days) than in the three splenectomy responders (20 days). Median time to treatment failure was significantly greater in the alpha interferon patients (greater than 18 months) than in the splenectomy patients (less than 1 month). Survival was no different since patients relapsing following splenectomy subsequently responded to alpha interferon. A significant decrease in leukemic bone marrow infiltration was observed in seven of ten patients receiving alpha interferon and in none of the patients undergoing splenectomy. Side effects, primarily infections, were more frequent in patients receiving interferon. Alpha interferon is preferable to splenectomy as initial treatment for hairy cell leukemia.     

Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Therapeutic and immunologic results

Hairy cell leukemia is a lymphoproliferative disorder characterized clinically by cytopenias. Standard therapy following variable periods of disease stability consists of splenectomy that often restores normal hematologic parameters for periods ranging from weeks to years. Fifteen patients (five without prior splenectomy or chemotherapy) were treated with 3 X 10(6) units per day of recombinant leukocyte A interferon and 14 of 15 patients completed eight weeks of therapy and were evaluated for response. There was one complete and 12 partial responses for an overall response rate of 93 percent. All of these patients' conditions have remained in complete or partial remissions and they continue to receive interferon with a median follow-up of six months. Coincident with the normalization of peripheral blood counts was a return of natural killer activity and normalization of immunologic surface markers as determined by monoclonal antibodies. This study confirms and extends earlier observations with natural alpha-interferon and indicates that recombinant leukocyte A interferon in low daily doses is also very effective treatment for hairy cell leukemia. In fact, it may be the best single modality of therapy for inducing both hematologic and immunologic recovery of these patients and deserves consideration as initial therapy.     

全血γ干扰素测定试验在承德地区结核病诊断价值研究

目的探讨全血γ干扰素测定试验(TB-IGRA)在承德地区结核分枝杆菌感染的临床价值。方法选取自2014年5月1日至2015年5月1日间,来中国人民解放军第二六六医院就诊和住院治疗的142例结核病患者、85例非活动性结核患者,均行全血特异性γ干扰素(IFN-γ)含量测定,同时与抗酸染色和血结核抗体检测进行平行比较分析。结果结核病患者体内γ干扰素(IFN-γ)水平显著高于非结核病患者,差异有统计学意义(P0.05);全血γ干扰素测定试验对结核分枝杆菌(MTB)感染者的敏感性为88.73%(126/142),特异性为88.24%(75/85);142例结核病患者中,抗酸染色和血结核抗体的阳性率分别为:41.55%(59/142)和65.49%(93/142),全血γ干扰素测定试验与抗酸染色、结核抗体阳性率差异有统计学意义(P0.01、P0.05)。结论全血γ干扰素测定试验可以快速、有效的诊断结核分枝杆菌感染患者,是一种适合本地区结核病诊断的试验方法。     

2'-Deoxycoformycin after failure of alpha-interferon in hairy cell leukemia

Alpha-interferon (IFN) and 2'-deoxycoformycin (dCF) both exhibit substantial activity in the treatment of hairy cell leukemia (HCL). Anecdotal reports have suggested that patients who failed IFN could achieve durable responses with dCF, although the frequency with which this was said to have occurred was unknown. We reviewed the available data on the responsiveness of HCL to dCF after IFN therapy by analyzing cases reported in the literature and those treated under the Special Exception mechanism of the National Cancer Institute, Division of Cancer Treatment. Of 60 such cases identified there were 22 (37%) "compete responses" and 22 (37%) "partial responses" for a total response rate of 74%. Responses appeared to be durable in many cases, lasting up to 2 years at the time of reporting. dCF is an active agent in HCL both as initial therapy and for the salvage of patients who have failed IFN. The relative activity of these two agents and the optimal strategies for their use are currently under investigation in ongoing clinical trials.     

γ-干扰素释放试验应用于结核病诊断的研究进展

结核病是我国重点控制的重大传染病之一,早期发现、早期治疗结核病患者是减少传播、控制结核病疫情的关键环节。近年来,结核感染的实验室诊断不断取得进展,尤以γ-干扰素为基础的免疫学诊断研究最为广泛。本文就γ-干扰素释放试验的产生、发展以及在结核病诊断中的研究进展进行了综述。     

乙型肝炎患者外周血白细胞膜γ干扰素受体1的变化及其临床意义

目的研究不同临床类型慢性乙型肝炎患者外周血白细胞膜γ干扰素受体1(IFN-γR1)反应的差异性及其临床意义。方法采用流式细胞技术及夹心酶联免疫吸附法检测53例慢性乙型肝炎患者外周血细胞膜IFN-γR1表达及血清IFN-γ水平变化,并与血生物化学指标、肝组织病理变化进行相关性分析。结果慢性重型肝炎淋巴细胞膜IFN-γR1表达水平显著高于正常对照[(28.89％±11.77％)与(9.23％±1.30％)],两者差异有显著性(Z=3.988,P<0.05)。各组间单核细胞膜IFN-γR1表达水平变化差异无显著性。肝硬化、重型肝炎两者血清IFN-γ水平较正常对照,差异有显著性升高,肝硬化、重型肝炎IFN-γ水平组内差异较大,组间无差异。慢性乙型肝炎患者淋巴细胞膜IFN-γR1与总胆红素显著相关(r=0.575,P<0.01),与肝组织炎症活动度显著相关(r=0.621,P<0.01)。结论慢性乙型肝炎淋巴细胞通过上调膜IFN-γR1参与免疫病理。     

Abnormalities in lymphocyte profile and specificity repertoire of patients with Waldenstrom's macroglobulinemia, multiple myeloma, and IgM monoclonal gammopathy of undetermined significance

The characteristics of T and B lymphocyte profile and B lymphocyte specificity repertoire were compared in patients with Waldenstrom's macroglobulinemia (WM), IgM monoclonal gammopathy of undetermined significance (IgM MGUS), multiple myeloma (MM), and age-matched normal subjects. Patients with MM had both significantly reduced frequency and number of sIg+ (surface Ig) B cells, whereas patients with WM and IgM MGUS had a reduced frequency but normal numbers of sIg+ B cells in circulation as detected in a capping assay. WM was distinguished by the large numbers of cells in the peripheral blood lymphocyte (PBL) pool that expressed CD9 (BA-2) and CD24 (BA-1) and were monoclonal, based on light chain analysis using flow cytometry. The profile of T lineage cells showed that the ratio of CD4:CD8 was significantly reduced in both MM and WM due to a reduction in the CD4 set. The CD4+ cells were qualitatively abnormal as well, with an enriched proportion of the 4B4+ (CDw29) subset and decreased proportion of the Lp220+ (CD45R) subset. This appeared to be an effect of the disease process on the relatively immature Lp220+ set. From clonal analysis, those patients with WM or IgM MGUS (unlike MM patients) did not exhibit enhanced reactivity with auto-Ig determinants, and most WM patients (7/8) and half of the IgM MGUS patients (3/6) did not have enriched proportions of B cells reactive to tetanus toxoid (TT). The TT-specific B cells in both WM and IgM MGUS, in contrast to MM, appeared fully functional in secretion of anti-TT IgM in vivo. We speculate that the more severe immunodeficiency in MM may be controlled or exacerbated by the presence of an anti-Ig network. The absence of this network in WM allows a relatively more effective immune response, but the immunodeficiency that is observed in these patients involves some abnormality in normal lymphocyte differentiation (is also present in MM).     

Role of gamma interferon and T cells in congenital Toxoplasma transmission

In the BALB/c mouse model, primary infection with Toxoplasma gondii during the second third of gestation leads to a high percentage of infected foetuses. However, immunity induced by infection contracted before pregnancy prevents parasites from crossing the placenta and completely protects the foetuses, as well as the pregnant women. In order to clarify the roles of CD4+, CD8+ T lymphocytes and IFN-gamma in this protection, pregnant BALB/c mice were treated with depleting monoclonal antibodies against CD4, CD8, IFN-gamma, or control antibody. Only the foetuses of the groups treated with anti-CD8 and anti-IFN-gamma antibodies developed congenital toxoplasmosis. The maternal production of IFN-gamma was depressed in the mice depleted of CD4 and CD8 cells (P < 0.001). Determination of the blood parasite load demonstrated that materno-foetal transmission of T. gondii correlates with maternal parasitaemia. Together, these results show that CD8+ T lymphocytes and IFN-gamma play an important role in protection against congenital toxoplasmosis during reinfection.     

Decreased production of interferon gamma by anti-CD3 monoclonal antibody and interleukin-2 -stimulated peripheral blood mononuclear cells in Hodgkin's disease

Summary. We have examined the production of interferon (IFN) gamma by peripheral blood mononuclear cells (PBMC) in 22 patients with Hodgkin's disease (HD) in active phase of the disease, 12 patients in clinical remission and 16 healthy subjects. The level of IFN gamma in supernatants of PBMC stimulated for 72 h with anti-CD3 monoclonal antibody (mAb), measured by sandwich enzyme immunoassay (ELISA) was 50.4 ± 2.3 U/ml in active phase; 137.0 ±7.4 U/ml in clinical remission patients; and 520.0 ± 10.0 U/ml in the controls; the difference between the groups was statistically significant. Co-stimulation with interleukin-2 (rIL-2) markedly amplified production of IFN gamma. The mean levels were 220.8 ±7.0U/ml, 590-7 ±3-6U/ml and 2111.1 ± 17.3 U/ml in active phase HD, clinical remission and controls, respectively, the difference between groups was statistically significant. The patients showed the same kinetic pattern as healthy individuals. Our results indicate that patients with HD have severely impaired TCR/CD3 activation pathway resulting in significantly depressed IFN gamma response to anti-CD3 mAb and anti-CD3 + rIL-2 in vitro stimulation and provide support for the possible clinical use of IFN gamma as an immunopotentiating agent in patients with HD.     

IgM myeloma and Waldenstrom's macroglobulinemia: a distinct clinical feature,histology, immunophenotype,and chromosomal abnormality

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone within the bone marrow. While the cause of myeloma is not known, interleukin 6 may play a role in driving myeloma cell proliferation. Waldenstrom's macroglobulinemia (WM) is a proliferative disease of B-lymphocytes. The cells have lymphoplasmacytoid features and secrete IgM. It is important to distinguish between IgM myeloma and WM as they have distinct clinical courses and prognoses, and treatment strategies are therefore different. The clinical characteristics of a patient diagnosed with IgM myeloma, and his excellent response to treatment are reported here.     

Experimental model for human intestinal microsporidiosis in interferon gamma receptor knockout mice infected by Encephalitozoon intestinalis

Interferon gamma receptor knockout mice developed a chronic infection when inoculated with spores of Encephalitozoon intestinalis which is a cause of intestinal microsporidiosis in AIDS patients. The infection was evaluated by enumeration of the spores of the parasite shed in the stools, histological examination and follow up over a period of six months. A dose-response was demonstrated since higher numbers of spores were excreted and more infection sites were found in mice which were given an increased quantity of parasites. In infected wild type mice, the number of excreted spores decreased until day 16 post-inoculation, then spores were detected sporadically in low numbers. These data confirmed the role of IFN-γ in the control of E. intestinalis infection. The infection was not lethal suggesting that other factors are involved in regulation of the parasite infection. This model, with the long survival time of the animals together with the measurable quantity of spores shed in the stools will be useful for testing potential therapeutical agents.     

IgM myeloma and Waldenstrom's macroglobulinemia: a distinct clinical feature,histology, immunophenotype,and chromosomal abnormality

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone within the bone marrow. While the cause of myeloma is not known, interleukin 6 may play a role in driving myeloma cell proliferation. Waldenstrom's macroglobulinemia (WM) is a proliferative disease of B‐lymphocytes. The cells have lymphoplasmacytoid features and secrete IgM. It is important to distinguish between IgM myeloma and WM as they have distinct clinical courses and prognoses, and treatment strategies are therefore different. The clinical characteristics of a patient diagnosed with IgM myeloma, and his excellent response to treatment are reported here.