Immune Recovery after Cyclophosphamide Treatment in Multiple Myeloma: Implication for Maintenance Immunotherapy

Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by clonal proliferation of malignant plasma cells. Increased numbers of regulatory T cells (Tregs) were determined in mouse models and in patients with MM, which correlated with disease burden. Thus, it became rational to target Tregs for treating MM. The effects of common chemotherapeutic drugs on Tregs are reviewed with a focus on cyclophosphamide (CYC). Studies indicated that selective depletion of Tregs may be accomplished following the administration of a low-dose CYC. We report that continuous nonfrequent administrations of CYC at low doses block the renewal of Tregs in MM-affected mice and enable the restoration of an efficient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence. Hence, distinctive time-schedule injections of low-dose CYC are beneficial for breaking immune tolerance against MM tumor cells

In Vivo Dynamical Interactions between CD4 Tregs, CD8 Tregs and CD4+CD25− Cells in Mice

BACKGROUND: Regulatory T cells (Tregs) were shown to be central in maintaining immunological homeostasis and preventing the development of autoimmune diseases. Several subsets of Tregs have been identified to date; however, the dynamics of the interactions between these subsets, and their implications on their regulatory functions are yet to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We employed a combination of mathematical modeling and frequent in vivo measurements of several T cell subsets. Healthy BALB/c mice received a single injection of either hCDR1--a tolerogenic peptide previously shown to induce Tregs, a control peptide or vehicle alone, and were monitored for 16 days. During this period, splenocytes from the treated mice were analyzed for the levels of CD4, CD25, CD8, CD28 and Foxp3. The collected data were then fitted to mathematical models, in order to test competing hypotheses regarding the interactions between the followed T cell subsets. In all 3 treatment groups, a significant, lasting, non-random perturbation of the immune system could be observed. Our analysis predicted the emergence of functional CD4 Tregs based on inverse oscillations of the latter and CD4(+)CD25(-) cells. Furthermore, CD4 Tregs seemed to require a sufficiently high level of CD8 Tregs in order to become functional, while conversion was unlikely to be their major source. Our results indicated in addition that Foxp3 is not a sufficient marker for regulatory activity. CONCLUSIONS/SIGNIFICANCE: In this work, we unraveled the dynamics of the interplay between CD4, CD8 Tregs and effector T cells, using, for the first time, a mathematical-mechanistic perspective in the analysis of Treg kinetics. Furthermore, the results obtained from this interdisciplinary approach supported the notion that CD4 Tregs need to interact with CD8 Tregs in order to become functional. Finally, we generated predictions regarding the time-dependent function of Tregs, which can be further tested empirically in future work

Exploring Takfir, Its Origins and Contemporary Use: The Case of Takfiri Approach in Daesh’s Media

Muslims have been the primary targets of Daesh’s attacks since 2014 in different countries such as Afghanistan, Iraq, and Syria. These attacks were based on its takfiri ideology. As Daesh official media and documents indicate, kufr (unbelief, infidelity) in Daesh’s approach is not limited to non-Muslims (original disbelievers), but Muslims are the most significant parts of kuffar (unbelievers) in its view and defined as incidental disbelievers. Through studying Daesh’s official documents and various Arabic, English, and Persian media productions, in an explanatory research, this article attempts to display Daesh’s takfiri approach toward Muslims and explains its historical and ideological roots, difference with Al-Qaeda’s takfiri approach, different approaches to takfir inside Daesh, main targets of Daesh’s takfir, and the reasons behinds its takfiri view. This article displays that for Daesh, the Muslims are limited only to Sunni Muslims who are accepting and following its approach. Other Sunni and non-Sunni Muslims are thus kuffar. This study also shows that the assertion of takfir has become a method for Daesh to discredit its opponents, such as Shi’a Muslims and other Muslim groups

The tolerogenic peptide, hCDR1, down-regulates the expression of interferon-α in murine and human systemic lupus erythematosus.

The tolerogenic peptide, hCDR1, ameliorated manifestations of systemic lupus erythematosus (SLE) via the immunomodulation of pro-inflammatory and immunosuppressive cytokines and the induction of regulatory T cells. Because type I interferon (IFN-α) has been implicated to play a role in SLE pathogenesis, we investigated the effects of hCDR1 on IFN-α in a murine model of SLE and in human lupus.(NZBxNZW)F1 mice with established SLE were treated with hCDR1 (10 weekly injections). Splenocytes were obtained for gene expression studies by real-time RT-PCR. hCDR1 down-regulated significantly IFN-α gene expression (73% inhibition compared to vehicle treated mice, p = 0.002) in association with diminished clinical manifestations. Further, hCDR1 reduced, in vitro, IFN-α gene expression in peripheral blood mononuclear cells (PBMC) of 10 lupus patients (74% inhibition compared to medium, p = 0.002) but had no significant effects on the expression levels of IFN-α in PBMC of primary anti-phospholipid syndrome patients or of healthy controls. Lupus patients were treated for 24 weeks with hCDR1 (5) or placebo (4) by weekly subcutaneous injections. Blood samples collected, before and after treatment, were frozen until mRNA isolation. A significant reduction in IFN-α was determined in hCDR1 treated patients (64.4% inhibition compared to pretreatment expression levels, p = 0.015). No inhibition was observed in the placebo treated patients. In agreement, treatment with hCDR1 resulted in a significant decrease of disease activity. IFN-α appears to play a role in the mechanism of action of hCDR1 since recombinant IFN-α diminished the immunomodulating effects of hCDR1 on IL-1β, TGFβ and FoxP3 gene expression.We reported previously that hCDR1 affected various cell types and immune pathways in correlation to disease amelioration. The present studies demonstrate that hCDR1 is also capable of down-regulating significantly (and specifically to lupus) IFN-α gene expression. Thus, hCDR1 has a potential role as a novel, disease specific treatment for lupus

Predictive Refined Computational Modeling of ACL Tear Injury Patterns

Anterior cruciate ligament (ACL) ruptures are prevalent knee injuries, with approximately 200,000 ruptures annually, and treatment costs exceed USD two billion in the United States alone. Typically, the initial detection of ACL tears and anterior tibial laxity (ATL) involves manual assessments like the Lachman test, which examines anterior knee laxity. Partial ACL tears can go unnoticed if they minimally affect knee laxity; however, they will progress to a complete ACL tear requiring surgical treatment. In this study, a computational finite element model (FEM) of the knee joint was generated to investigate the effect of partial ACL tears under the Lachman test (GNRB® testing system) boundary conditions. The ACL was modeled as a hyperelastic composite structure with a refined representation of collagen bundles. Five different tear types (I–V), classified by location and size, were modeled to predict the relationship between tear size, location, and anterior tibial translation (ATT). The results demonstrated different levels of ATT that could not be manually detected. Type I tears demonstrated an almost linear increase in ATT, with the growth in tear size ranging from 3.7 mm to 4.2 mm, from 25% to 85%, respectively. Type II partial tears showed a less linear incline in ATT (3.85, 4.1, and 4.75 mm for 25%, 55%, and 85% partial tears, respectively). Types III, IV, and V maintained a nonlinear trend, with ATTs of 3.85 mm, 4.2 mm, and 4.95 mm for Type III, 3.85 mm, 4.25 mm, and 5.1 mm for Type IV, and 3.6 mm, 4.25 mm, and 5.3 mm for Type V, for 25%, 55%, and 85% partial tears, respectively. Therefore, for small tears (25%), knee stability was most affected when the tears were located around the center of the ligament. For moderate tears (55%), the effect on knee stability was the greatest for tears at the proximal half of the ACL. However, severe tears (85%) demonstrated considerable growth in knee instability from the distal to the proximal ends of the tissue, with a substantial increase in knee instability around the insertion sites. The proposed model can enhance the characterization of partial ACL tears, leading to more accurate preliminary diagnoses. It can aid in developing new techniques for repairing partially torn ACLs, potentially preventing more severe injuries

Effects of treatment with hCDR1 on SLE manifestations in mice.

a<p>SLE-afflicted (NZB×NZW)F1 mice (10–12 mice per group in 4 independent experiments) were treated with weekly subcutaneous injections of the vehicle, hCDR1, or a control (scrambled peptide) for 10 weeks.</p>b<p>Results are of sera from mice that were bled after the end of treatment. Dilution of sera 1∶1250.</p>c<p>Statistical evaluation was based on the Mann-Whitney U test to compare post –treatment effects between the vehicle –treated groups and the remaining treatment groups.</p>d<p>Proteinuria was always measured at about the same time of day and all mice in an experimental cohort were tested together.</p>e<p>Immune complex deposits (ICD) were assessed at sacrifice.</p>f<p>p = 0.04, 0.02 and 0.0001 between the control peptide and hCDR1 treated mice for dsDNA specific antibodies, proteinuria and ICD, respectively.</p