Type I IFNs promote the early IFN‐γ response and the IL‐10 response in Leishmania mexicana infection

The protozoan parasite Leishmania mexicana causes chronic cutaneous disease in humans and most mouse strains. We previously showed that STAT4‐deficient mice, but not IL‐12p40‐deficient mice, have more parasites and progressively growing lesions unlike those of wild‐type mice, the lesions and parasite burdens of which plateau by 10–12 weeks post‐infection. This demonstrates a STAT4‐dependent, IL‐12/IL‐23‐independent pathway of parasite control. Type I IFNs are important in viral and other infections and can activate STAT4. We found that IFN‐α/βR‐deficient mice have a nonpersistent, early IFN‐γ defect, and a persistent, early IL‐10 defect, without changes in serum IL‐12 or LN‐derived nitric oxide. We found less IL‐10 per cell in CD25⁺CD4⁺ T cells and possibly fewer IL‐10‐producing cells in the draining LN of IFN‐α/βR‐deficient vs. wild‐type mice. IFN‐α/βR‐deficient mice have chronic, nonprogressive disease, like wild‐type mice, suggesting that IL‐10 and IFN‐γ defects may balance each other. Our data indicate that although type I IFNs help promote early Th1 responses, they are not the missing activators of STAT4 responsible for partial control of L. mexicana. Also, the lack of lesion resolution in IFN‐α/βR‐deficient mice despite lower IL‐10 levels indicates that other pathways independent of T cell IL‐10 help prevent an IL‐12‐driven clearance of parasites.     

Elevated expression of interleukin‐7 receptor in inflamed joints mediates interleukin‐7–induced immune activation in rheumatoid arthritis

Objective

To evaluate the expression and functional ability of the high‐affinity interleukin‐7 receptor (IL‐7Rα) in patients with rheumatoid arthritis (RA).

Methods

Expression of IL‐7Rα and IL‐7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL‐7Rα expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL‐7Rα^bright and IL‐7Rα^dim/− T cells was measured. In addition, we examined IL‐7R blockade with soluble human IL‐7Rα (hIL‐7Rα) in the prevention of immune activation of peripheral blood mononuclear cells.

Results

We found significantly higher IL‐7Rα expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL‐7Rα expression correlated significantly with the levels of CD3 and IL‐7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL‐7Rα. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL‐7Rα, although less prominently than T cells. We found that peripheral blood IL‐7Rα^bright T cells that did not express FoxP3 were highly proliferative as compared with IL‐7Rα^dim/− T cells that did express high levels of FoxP3. Soluble hIL‐7Rα inhibited IL‐7–induced proliferation and interferon‐γ production by mononuclear cells from RA patients.

Conclusion

Our data suggest that enhanced expression of IL‐7Rα and IL‐7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL‐7R–mediated immune activation by soluble hIL‐7Rα further indicates an important role of IL‐7Rα in inflammatory responses in RA, suggesting IL‐7Rα as a therapeutic target for immunotherapy in RA.

     

Lymphotoxin‐β receptor in microenvironmental cells promotes the development of T‐cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

Lymphotoxin‐mediated activation of the lymphotoxin‐β receptor (LTβR; LTBR) has been implicated in cancer, but its role in T‐cell acute lymphoblastic leukaemia (T‐ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)‐α and LTβ (LTA, LTB) are expressed in T‐ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL‐JAK2 transgenic mouse model of cortical/mature T‐ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T‐ALL. Surface LTα₁β₂ protein is expressed in primary mouse T‐ALL cells, but only in the absence of microenvironmental LTβR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr‐expressing but not Ltbr‐deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T‐ALL, inactivation of Ltbr results in a significant delay in TEL‐JAK2‐induced leukaemia onset. Moreover, young asymptomatic TEL‐JAK2;Ltbr^?/? mice present markedly less leukaemic thymocytes than age‐matched TEL‐JAK2;Ltbr^+/+ mice and interference with LTβR function at this early stage delayed T‐ALL development. We conclude that LT expression by T‐ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.     

The role of IL‐1β in reduced IL‐7 production by stromal and epithelial cells: a model for impaired T‐cell numbers in the gut during HIV‐1 infection

Abstract. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F (Karolinska Institutet, Stockholm, Sweden; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; San Raffaele Scientific Institute, Milan, Italy). The role of IL‐1β in reduced IL‐7 production by stromal and epithelial cells: a model for impaired T‐cell numbers in the gut during HIV‐1 infection. J Intern Med 2010; 268 : 181–193. Objectives. Interleukin (IL)‐7 is a key cytokine in T‐cell homeostasis. Stromal cells, intestinal epithelial cells and keratinocytes are known to produce this cytokine. The mechanisms and cellular factors regulating IL‐7 production are still unclear. We assessed whether IL‐1β and interferon (IFN)‐γ, cytokines produced during inflammatory conditions, may impact on IL‐7 production. Design. We used human intestinal epithelial cells (DLD‐1 cell line) and bone marrow stromal cells (HS27 cell line), known to produce IL‐7; IL‐7 production was evaluated at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL‐1β and/or IFN‐γ leads to changes in the gene expression of cytokines, Toll‐like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole‐genome microarray Human Gene 1.0 ST. Results. We found that IFN‐γ enhanced the expression of IL‐7 mRNA (P < 0.001) in both cell lines. IL‐1β treatment led to a significant down‐regulation (P < 0.001) of IL‐7 mRNA expression in both cell lines. The IL‐7 concentration in supernatants collected from treated DLD‐1 and HS27 cell cultures reflected the trend of IL‐7 mRNA levels. The gene profiles revealed dramatic changes in expression of cytokines and their receptors (IL‐7/IL‐7Rα; IL‐1α,IL‐1β/IL‐1R1; IFN‐γ/IFN‐γR1), of IFN regulatory factors (IRF‐1 and 2), of TLRs and of important chemo‐attractants for T cells. The microarray results were verified by additional methods. Conclusions. Our results are discussed in the setting of inflammation and T‐cell survival in the gut compartment during HIV‐1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL‐7 homeostasis and homing of T cells.     

Baseline sensitivity of T cells to alpha‐IFN correlates with sustained virological response to IFN‐based triple therapy in HCV infection

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV‐infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein‐3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho‐STAT1 level as read‐out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho‐STAT1 and interferon‐stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho‐STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho‐STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN‐sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost‐effectiveness strategies of treatment by identifying patients who will or will not respond to IFN‐based treatments.     

Blockade of the interleukin‐7 receptor inhibits collagen‐induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators

Objective

To study the effects of interleukin‐7 receptor α‐chain (IL‐7Rα) blockade on collagen‐induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators.

Methods

We studied the effect of anti–IL‐7Rα antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell–associated cytokines were measured in supernatants of lymph node cell cultures.

Results

Anti–IL‐7Rα treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti–IL‐7Rα. IL‐7Rα blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell–associated cytokines (interferon‐γ, IL‐5, and IL‐17). IL‐7Rα blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor α, IL‐1β, IL‐6, matrix metalloproteinase 9, and RANKL. IL‐7Rα blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered.

Conclusion

Blockade of IL‐7Rα potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell–associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL‐7R–driven immunity in experimental arthritis and indicates the therapeutic potential of IL‐7Rα blockade in human arthritic conditions.

     

Mutant calreticulin‐expressing cells induce monocyte hyperreactivity through a paracrine mechanism

Mutations in the calreticulin gene (CALR) were recently identified in approximately 70–80% of patients with JAK2‐V617F‐negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C‐terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium‐binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL‐3‐independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2‐V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll‐like receptor agonist. These effects are not dependent on the novel C‐terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2‐V617F‐negative essential thrombocytosis and primary myelofibrosis. Am. J. Hematol. 91:211–219, 2016. © 2015 Wiley Periodicals, Inc.     

NOTCH1 mutations are associated with favourable long‐term prognosis in paediatric T‐cell acute lymphoblastic leukaemia: a retrospective study of patients treated on BCH‐2003 and CCLG‐2008 protocol in China

Activating mutations of NOTCH1 are a common occurrence in T‐cell acute lymphoblastic leukaemia (T‐ALL), but its impact on T‐ALL treatment is still controversial. In this study, the incidence, clinical features, and prognosis of 92 Chinese children with T‐ALL treated using the Beijing Children's Hospital‐2003 and Chinese Childhood Leukaemia Group‐2008 protocols were analysed. NOTCH1 mutations were found in 42% of T‐ALL patients and were not associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. However, proline, glutamate, serine, threonine (PEST)/transactivation domain (TAD) mutations were associated with younger age (15/16 mutant vs. 48/76 wild‐type, P = 0·018) and more central nervous system involvement (4/16 mutant vs. 3/76 wild‐type, P = 0·016); while heterodimerization domain (HD) mutations were associated with KMT2A‐MLLT1 (MLL‐ENL; 4/30 mutant vs. 1/62 wild‐type, P = 0·037). Furthermore, prognosis was better in patients with NOTCH1 mutations than in those with wild‐type NOTCH1 (5‐year event‐free survival [EFS] 92·0 ± 4·5% vs. 64·0 ± 7·1%; P = 0·003). Long‐term outcome was better in patients carrying HD mutations than in patients with wild‐type HD (5‐year EFS 89·7 ± 5·6% vs. 69·3 ± 6·2%; P = 0·034). NOTCH1 mutations and MRD at day 78 were independent prognostic factors. These findings indicate that NOTCH1 mutation predicts a favourable outcome in Chinese paediatric patients with T‐ALL on the BCH‐2003 and CCLG‐2008 protocols, and may be considered a prognostic stratification factor.     

Immunophenotypic analysis of T‐acute lymphoblastic leukemia. A CD5‐based ETP‐ALL perspective of non‐ETP T‐ALL

T‐cell antigens [CD5,CD1a,CD8] define early T‐cell precursor acute lymphoblastic leukemia (ETP‐ALL). To understand immature T‐ALL of which ETP‐ALL is part, we used these antigens to subcategorize non‐ETP T‐ALL for examining expression of myeloid/stem cell antigens (M/S) and clinical features. Using CD5 (+/?) to start categorization, we studied 69 routinely immunophenotyped patients with T‐ALL. CD5^? was a homogenous (CD8,CD1a)^? M/S⁺ ETP‐ALL group (n = 9). CD5⁺ cases were (CD8,CD1a)^? pre‐T‐ALL (n = 22) or (CD8,CD1a)⁺ (n = 38) thymic/cortical T‐ALL; M/S⁺ 20/22 (90.91%) in former and 22/38 (57.89%) in latter (P = 0.007). ETP‐ and pre‐T‐ALL together (CD1a^?,CD5^?/+ immature T‐ALL group) were nearly always M/S⁺ (29/31; 93.55%). In multivariate analysis, only ETP‐ALL predicted poor overall survival (P = 0.02). We conclude (i) CD5 negativity in T‐ALL almost always means ETP‐ALL. CD1a and CD8 negativity, as much as CD5, marks immaturity in T‐ALL, and the CD5^+/?/CD1a^?/CD8^? immature T‐ALL group needs further study to understand the biology of the T‐ALL–myeloid interface. (ii) ETP‐ALL patients may be pre‐T‐ALL if CD2⁺; CD2⁺, conversely, CD5^?/CD1a^?/CD8^? pre‐T ALL patients are ETP‐ALL. (iii) Immunophenotypic workup of T‐ALL must not omit CD1a, CD5, CD8 and CD2, and positivity of antigens should preferably be defined as recommended for ETP‐ALL, so that this entity can be better evaluated in future studies of immature T‐ALL, a group to which ETP‐ALL belongs. (iv) ETP‐ALL has poor prognosis.     

N‐acetyl‐L‐cysteine improves mesenchymal stem cell function in prolonged isolated thrombocytopenia post‐allotransplant

Prolonged isolated thrombocytopenia (PT) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Murine studies and in vitro experiments suggest that mesenchymal stem cells (MSCs) can, not only to support haematopoiesis, but also preferentially support megakaryocytopoiesis in bone marrow (BM). However, little is known about the quantity and function of BM MSCs in PT patients. In a case‐control study, we found that BM MSCs from PT patients exhibited significantly reduced proliferative capacities, increased reactive oxygen species and senescence. Antioxidant (N‐acetyl‐L‐cysteine, NAC) treatment in vitro not only quantitatively and functionally improved BM MSCs derived from PT patients through down‐regulation of the p38 (also termed MAPK14) and p53 (also termed TP53) pathways but also partially rescued the impaired ability of BM MSCs to support megakaryocytopoiesis. Subsequently, a pilot study showed that the overall response of NAC treatment was obtained in 7 of the enrolled PT patients (N = 10) without significant side effects. Taken together, the results indicated that dysfunctional BM MSCs played a role in the pathogenesis of PT and the impaired BM MSCs could be improved by NAC in vitro. Although requiring further validation, our data indicate that NAC might be a potential therapeutic approach for PT patients after allo‐HSCT.     

HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis

Background

We hypothesized that there may be a correlation between the interleukin‐7 (IL‐7)/IL‐7 receptor (IL‐7R) regulatory system and parameters of T‐cell homeostasis in HIV‐infected long‐term nonprogressors (LTNPs) as compared with patients with disease progression.

Methods

The possibility of a correlation between T‐cell homeostatic parameters and IL‐7/IL‐7R was investigated in 22 LTNPs (CD4 count ≥500 cells/μL for >10 years) vs. HIV‐positive patients at different disease stages [12 early: CD4 count ≥400 cells/μL; 15 late (AIDS‐presenters): CD4 count ≤150 cells/μL].

Results

Compared with early‐stage HIV‐positive patients, LTNPs displayed a higher circulating IL‐7 concentration (P=0.05), which was positively associated with higher IL‐7Rα expression and a higher T‐cell receptor excision circle (TREC) content specifically within CD4 cells (P<0.05). Compared with late‐stage disease patients, early‐stage disease patients displayed a lower IL‐7 concentration (P<0.01) and higher percentages of IL‐7Rα⁺ CD4 and CD8 cells (P=0.05). IL‐7 was positively correlated with the percentage of TREC⁺ CD4 cells (P<0.01), which translated into a higher percentage of naïve CD4 cells in early‐stage disease patients than in late‐stage disease patients; however, the CD4 cells in early‐stage disease patients were less enriched in recent thymic emigrants (RTEs) compared with LTNPs (P<0.05). In late‐stage AIDS‐developing patients, substantially increased IL‐7 was correlated with a decreased percentage of IL‐7Rα⁺ CD4 cells (P=0.01), which resulted in these patients having a significantly lower percentage of naïve T cells (P<0.01) and a significantly lower content of TREC (P<0.01) than the other patients.

Conclusions

The maintenance of high CD4 cell counts in LTNPs was associated with a specific IL‐7/IL‐7R pattern characterized by increased IL‐7 and highest IL‐7Rα‐expressing CD4 cells relative to other patients. Compared with patients with late‐stage disease, LTNPs displayed a phenotypically naïve, less activated CD4 cell pool highly enriched in RTEs, suggesting the existence of a compensatory IL‐7‐mediated pathway specifically sustaining peripheral CD4 counts.

     

IL‐6 promotes CD4+ T‐cell and B‐cell activation during Plasmodium infection

Humoral immunity develops in the spleen during blood‐stage Plasmodium infection. This elicits parasite‐specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4⁺ T cells, B cells, interleukin (IL)‐21 and ICOS. IL‐6, a cytokine readily detected in Plasmodium‐infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection‐induced IL‐6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild‐type and IL‐6^?/? mice, we found that IL‐6 helped to control parasites during primary infection. IL‐6 promoted early production of parasite‐specific IgM but not IgG. Notably, splenic CD138⁺ plasmablast development was more dependent on IL‐6 than germinal centre (GC) B‐cell differentiation. IL‐6 also promoted ICOS expression by CD4⁺ T cells, as well as their localization close to splenic B cells, but was not required for early Tfh‐cell development. Finally, IL‐6 promoted parasite control, IgM and IgG production, GC B‐cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL‐6 promotes CD4⁺ T‐cell activation and B‐cell responses during blood‐stage Plasmodium infection, which encourages parasite‐specific antibody production.     

Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: Identification of the interleukin‐7 signaling pathway in tissues with lymphoid neogenesis

Objective

In ∼25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures.

Methods

Gene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real‐time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin‐7 (IL‐7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies.

Results

Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin α and β messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell– and B cell–specific pathways, Fcε receptor type I signaling in mast cells, and IL‐7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL‐7 receptor α (IL‐7Rα)/IL‐2Rγ chains and IL‐7. Protein expression of IL‐7 in RA tissues was localized within fibroblast‐like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles.

Conclusion

Activation of the IL‐7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue.

     

Reversing interleukin‐2 inhibition mediated by anti–double‐stranded DNA autoantibody ameliorates glomerulonephritis in MRL‐lpr/lpr mice

Objective

Our previous study demonstrated that anti–double‐stranded DNA (anti‐dsDNA) antibodies involved in lupus nephritis down‐regulate the production of interleukin‐2 (IL‐2) in T cells, which in turn, contributes to the defective production of cytotoxic cells and to activation‐induced cell death in vitro. To reveal novel molecular targets for lupus therapy, the molecular mechanisms of IL‐2 down‐regulation by anti‐dsDNA were studied.

Methods

Anti‐dsDNA monoclonal antibody (mAb) 9D7 was used to study the molecular mechanisms of IL‐2 production in vitro. Treatment with arginine‐rich peptide, a penetration inhibitor, was used to verify the effect of internalization of anti‐dsDNA on the production of IL‐2. The signaling pathway for IL‐2 expression induced by anti‐dsDNA was analyzed by using kinase inhibitors. The therapeutic effects of these inhibitors were evaluated in MRL‐lpr/lpr mice.

Results

Inhibition of IL‐2 production in activated Jurkat cells and human T cells pretreated with mAb 9D7 was reversed by treatment with the arginine‐rich peptide. Levels of pAkt and phosphorylated glycogen synthase kinase 3 (pGSK‐3) were reduced in activated Jurkat cells that had been pretreated with mAb 9D7. The inhibition of IL‐2 production by mAb 9D7 was counteracted by pretreating the cells with LiCl (a GSK‐3 inhibitor). However, IL‐2 reduction was not recovered in the cells pretreated with ERK and JNK inhibitors. Furthermore, MRL‐lpr/lpr mice injected with LiCl or with arginine‐rich peptide restored the IL‐2 production and reduced the manifestations of lupus.

Conclusion

These findings suggest that penetration of T cells by anti‐dsDNA may inhibit IL‐2 production by activating GSK‐3. Moreover, blocking GSK‐3 activation as well as inhibiting anti‐dsDNA penetration is a potential therapeutic approach for lupus.

     

Recombinant IL‐7/HGFβ hybrid cytokine separates acute graft‐versus‐host‐disease from graft‐versus‐tumour activity by altering donor T cell trafficking

Given that donor T cells from a transplant contribute both the desired graft‐versus‐tumour (GVT) effect and detrimental graft‐versus‐host disease (GVHD), strategies to separate GVHD and GVT activity are a major clinical goal. We have previously demonstrated that in vivo administration of a recombinant (r)IL‐7/HGFβ hybrid cytokine, consisting of interleukin‐7 (IL‐7, IL7) and the β‐chain of hepatocyte growth factor (HGFβ), significantly inhibits the growth of cancer cells in murine tumour models. The antit‐umour effect of rIL‐7/HGFβ is related to a marked infiltration T cells in the tumour tissues. We have also shown that GVHD was not induced in rIL‐7/HGFβ‐treated T cell‐depleted allogeneic haematopoietic stem cell transplantation (HSCT) recipients. We show here that, in T cell‐replete allogeneic HSCT murine models, rIL‐7/HGFβ attenuated acute GVHD (aGVHD), while promoting GVT activity. This was related to an alteration of donor T cell trafficking, with an increased infiltration of donor T cells into tumour tissues and the lympho‐haematopoietic system but decreased number of the T cells in the GVHD target organs. Therefore, rIL‐7/HGFβ may offer a new tool to alleviate aGVHD while prompting GVT, and to study the molecular regulation of T cell trafficking.