Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.     

A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity

Clinical studies of idiotype (Id) vaccination in patients with lymphoma have established a correlation between the induced anti-Id antibody responses and favorable clinical outcomes. To streamline the production of an Id vaccine, we engineered a small diabody (Db) molecule containing both a B-cell-targeting moiety (anti-CD19) and a lymphoma Id. This molecule (αCD19-Id) was designed to penetrate lymph nodes and bind to noncognate B cells to form an antigen presentation array. Indeed, the αCD19-Id molecule accumulated on B cells in vivo after s.c. administration. These noncognate B cells, decorated with the diabody, could then stimulate the more rare Id-specific B cells. Peptide epitopes present in the diabody linker augmented the response by activating CD4(+) helper T cells. Consequently, the αCD19-Id molecule induced a robust Id-specific antibody response and protected animals from tumor challenge. Such diabodies are produced in a cell-free protein expression system within hours of amplification of the specific Ig genes from the B-cell tumor. This customized product can now be available to vaccinate patients before they receive other, potentially immunosuppressive, therapies.     

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma

Human malignant pleural mesothelioma (MPM) is considered a rare tumor, but recent estimations indicate that one-quarter million people will die of this neoplasm in Europe in the next three decades. The mineral asbestos is considered the main causative agent of this neoplasm. MPM is largely unresponsive to conventional chemotherapy/radiotherapy. In addition to asbestos exposure, genetic predisposition to asbestos carcinogenesis and to simian virus (SV)40 infection has also been suggested. SV40 is a DNA tumor virus found in some studies to be associated at high prevalence with MPM. SV40 sequences have also been detected, although at a lower prevalence than in MPM, in blood specimens from healthy donors. However, some studies have failed to reveal SV40 footprints in MPM and its association with this neoplasm. These conflicting results indicate the need for further investigations with new approaches. We report on the presence of antibodies in serum samples from patients affected by MPM that specifically react with two different SV40 mimotopes. The two SV40 peptides used in indirect ELISAs correspond to viral capsid proteins. ELISA with the two SV40 mimotopes gave overlapping results. Our data indicate that in serum samples from MPM-affected patients (n = 97), the prevalence of antibodies against SV40 viral capsid protein antigens is significantly higher (26%, P = 0.043) than in the control group (15%) represented by healthy subjects (n = 168) with the same median age (66 y) and sex. Our results suggest that SV40 is associated with a subset of MPM and circulates in humans.     

Significant association of deficiency of hemoglobin, iron and vitamin B12, high homocysteine level, and gastric parietal cell antibody positivity with atrophic glossitis

J Oral Pathol Med (2012) 41 : 500–504 Background: Atrophic glossitis (AG) is considered to be a marker of nutritional deficiency. In this study, we evaluated whether there was an intimate association of the deficiency of hemoglobin, iron, vitamin B12 or folic acid, high blood homocysteine level, and serum gastric parietal cell antibody (GPCA) positivity with AG. Methods: The blood hemoglobin, iron, vitamin B12, folic acid, and homocysteine concentrations and the serum GPCA level in 176 AG patients were measured and compared with the corresponding levels in 176 age‐ and sex‐matched healthy control subjects. Results: We found that 39 (22.2%), 47 (26.7%), 13 (7.4%), and 3 (1.7%) AG patients had deficiencies of Hb (men < 13 g/dl, women < 12 g/dl), iron (<60 μg/dl), vitamin B12 (<200 pg/ml), and folic acid (<4 ng/ml), respectively. Moreover, 38 (21.6%) AG patients had abnormally high blood homocysteine level, and 47 (26.7%) AG patients had serum GPCA positivity. AG patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency, of abnormally elevated blood homocysteine level, or of serum GPCA positivity than healthy control subjects (all P‐values = 0.000). However, no significant difference in frequency of folic acid deficiency was found between AG patients and healthy control subjects. Conclusion: We conclude that there is a significant association of deficiency of hemoglobin, iron and vitamin B12, abnormally high blood homocysteine level, and serum GPCA positivity with AG.     

CD48 as a novel molecular target for antibody therapy in multiple myeloma

Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.     

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia

Background

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.

Design and Methods

Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.

Results

Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6–65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.

Conclusions

Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.     

Nodo-paranodopathy: Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies

In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain–Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region.     

Daclizumab: humanized monoclonal antibody to the interleukin-2 receptor

Daclizumab is a humanized antibody that binds to the α-chain of the interleukin-2 receptor and blocks the action of interleukin-2. It is approved for the prevention of organ allograft rejection using five 1 mg/kg doses every second week, starting at the time of transplant. Since approval, activity has primarily focused on the efficacy of shorter courses, typically two doses, and its use in steroid or calcineurin inhibitor elimination immunosuppressive protocols. In small trials, it appears that two doses are safe, effective and allow sparing of other toxic drugs. Outside the field of transplantation, the drug has been tested in a variety of autoimmune diseases including uveitis, diabetes, multiple sclerosis, ulcerative colitis and various dermatologic diseases. A new subcutaneous formulation is being developed to facilitate chronic dosing in these autoimmune diseases.     

Current status of monoclonal antibody therapy for the treatment of inflammatory bowel disease

Crohn’s disease and ulcerative colitis are complex diseases that have required the use of multiple modalities to aid in treatment. With an increasing understanding of the underlying pathogenetic mechanisms and identification of specific therapeutic targets, monoclonal antibody treatment has been an ideal strategy for inducing and maintaining remission in these patients. This article addresses approved agents and the supporting data justifying their use in Crohn’s disease and ulcerative colitis, the safety of and immunologic reactions to these agents, as well as newer agents for treatment.     

An update on treatment strategies for common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunological disease with variable severity, ranging from mild forms of infections to chronic progressive complications. The hallmark of this disorder is hypogammaglobulinemia due to an unknown molecular defect in immune regulation. The primary clinical manifestations are recurrent infections that may lead to structural damage of affected organs. Adequate intravenous immunoglobulin (Ig) therapy has dramatically changed the prognosis of this disorder, and the advent of home subcutaneous Ig therapy has further improved the quality of life of these patients. Aberrant T-cell functions predispose to autoimmune, inflammatory and lymphoproliferative complications, as well as malignancies in a variable percentage of CVID patients. Immunosuppressive anti-inflammatory therapies and chemotherapy are used, although always in conjunction with adequate replacement Ig therapy and adjunct antimicrobial prophylaxis. Any organ can be involved and therefore a multidisciplinary approach to the management of this disorder is essential.