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Summary: Patients with sickle cell disease (SCD) are considered to be immunocompromised, yet data on the antibody response to SARS‐CoV‐2 vaccination in SCD is limited. We investigated anti‐SARS‐CoV‐2 IgG titres and overall neutralizing activity in 201 adults with SCD and demographically matched non‐SCD controls. Unexpectedly, patients with SCD generate a more robust and durable COVID‐19 vaccine IgG response compared to matched controls, though the neutralizing activity remained similar across both cohorts. These findings suggest that patients with SCD achieve a similar antibody response following COVID‐19 vaccination compared to the general population, with implications for optimal vaccination strategies for patients with SCD. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is an immunocompromised condition and patients with SCD may have a reduced immune response to certain vaccinations. The report by Nakahara et al. demonstrated that SCD patients exhibited elevated and more sustained IgG production following COVID‐19 vaccination, when compared to healthy controls. This suggests that the immune response to vaccinations may vary among different types of vaccines in individuals with SCD. Commentary on: Nakahara et al. Enhanced IgG immune response to COVID‐19 vaccination in patients with sickle cell disease. Br J Haematol 2023;202:937–941. [ABSTRACT FROM AUTHOR]

Summary: Patients with transfusion‐dependent thalassaemia (TDT) are considered an at increased‐risk population for severe and/or morbid coronavirus disease 2019 (COVID‐19) infection. Timely vaccination is the main preventive method for severe COVID‐19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population. [ABSTRACT FROM AUTHOR]

Summary: We have vaccinated 392 patients with two doses of mRNA COMIRNATY vaccine with an overall antibody response of 70% (best in cMPN, worst in CLL). We have then vaccinated 80 patients who did not achieve seroconversion or were low responders with a third dose of COMIRNATY vaccine. Our first results show promise, especially for patients on anti‐CD38 therapy. [ABSTRACT FROM AUTHOR]

Summary: Patients affected by lymphoid malignancies (LM) are frequently immune‐compromised, suffering increased mortality from COVID‐19. This prospective study evaluated serological and T‐cell responses after complete mRNA vaccination in 263 patients affected by chronic lymphocytic leukaemia, B‐ and T‐cell lymphomas and multiple myeloma. Results were compared with those of 167 healthy subjects matched for age and sex. Overall, patient seroconversion rate was 64·6%: serological response was lower in those receiving anti‐cancer treatments in the 12 months before vaccination: 55% vs 81·9% (P < 0·001). Anti‐CD20 antibody plus chemotherapy treatment was associated with the lowest seroconversion rate: 17·6% vs. 71·2% (P < 0·001). In the multivariate analysis conducted in the subgroup of patients on active treatment, independent predictors for seroconversion were: anti‐CD20 treatment (P < 0·001), aggressive B‐cell lymphoma diagnosis (P = 0·002), and immunoglobulin M levels <40 mg/dl (P = 0·030). The T‐cell response was evaluated in 99 patients and detected in 85 of them (86%). Of note, 74% of seronegative patients had a T‐cell response, but both cellular and humoral responses were absent in 13·1% of cases. Our findings raise some concerns about the protection that patients with LM, particularly those receiving anti‐CD20 antibodies, may gain from vaccination. These patients should strictly maintain all the protective measures. [ABSTRACT FROM AUTHOR]

Summary: Treatment of relapsed/resistant acute myeloid leukaemia (AML) remains a significant area of unmet patient need, the outlook for most patients remaining extremely poor. A promising approach is to augment the anti‐tumour immune response in these patients; most cancers do not activate immune effector cells because they express immunosuppressive ligands. We have previously shown that CD200 (an immunosuppressive ligand) is overexpressed in AML and confers an inferior overall survival compared to CD200low/neg patients. Here we show that a fully human anti‐CD200 antibody (TTI‐CD200) can block the interaction of CD200 with its receptor and restore AML immune responses in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The article offers information on the Epstein–Barr virus (EBV) is integrated into the malignant Hodgkin Reed-Sternberg cell DNA in a subset of tumours, defining a subtype designated EBV+ HL. It mentions Epstein–Barr virus infects B lymphocytes and has a typical Herpesvirus family virus life cycle of latency and reactivation; and also mentions Hodgkin lymphoma (HL) patients have an abnormal cellular response to EBV antigens and a higher EBV viral load compared to unaffected individuals.

In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease ( GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor ( MRD) transplants. Dose reduction in matched unrelated donor ( MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants. [ABSTRACT FROM AUTHOR]

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia ( WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M ( IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials. [ABSTRACT FROM AUTHOR]

NKG2D ( KLRK1) is an activating receptor on natural killer ( NK) and T-cells and binds a diverse panel of polymorphic ligands encoded by the MIC and RAET1 gene families. We studied the clinical importance of retinoic acid early transcript-1 ( RAET1) polymorphism in allogeneic stem cell transplantation ( SCT) by determining the frequency of 18 single nucleotide polymorphisms ( SNPs) and individual RAET1 alleles in 371 patient-donor pairs and relating this to clinical outcome. A strong association was observed between the presence of five SNPs within the patient RAET1L ( ULBP6) gene and relapse-free survival and overall survival. Two common alleles of RAET1L were determined and the presence of the protective RAET1L*02 allele in the patient was associated with a relapse-free survival of 44% at 8 years compared with just 25% in patients who lacked a RAET1L*02 allele ( P < 0·001). Overall survival at this time was 55% in those with RAET1L*02 allele compared to 39% in patients who lacked a RAET1L*02 allele ( P = 0·003). These novel findings indicate a critical role for NKG2D- RAET1L interactions in determining SCT clinical outcome and show RAET1L may have an important influence on regulating the strength of the alloreactive immune response. The data will be of value in guiding the development of future transplant therapy protocols. [ABSTRACT FROM AUTHOR]

Patients with multiple myeloma ( MM) undergoing high dose therapy and autologous stem cell transplantation ( SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens ( CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine ( Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza- Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion ( ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow ( n = 4) or CD138+ cells ( n = 2). CTA ( CTAG1 B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT. [ABSTRACT FROM AUTHOR]

Summary Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction. [ABSTRACT FROM AUTHOR]

Summary The occurrence of alloantibodies against Factor VIII (FVIII) is the main iatrogenic complication in haemophilia A (HA). Anti-FVIII autoantibodies may also spontaneously appear in non-HA patients, leading to acquired haemophilia A. In both contexts, the antibody response against FVIII is complex and difficult to analyse due to the lack of suitable tools. Our purpose was to comprehensively map, at the amino acid level, discontinuous epitopes of the C2 domain of FVIII targeted by patients' antibodies. We synthesized 33 synthetic peptides, which were predicted by the bioinformatic algorithm PEPOP to mimic C2 domain discontinuous epitopes. Using an inhibition assay based on the x-MAP technology, we evaluated their ability to block the binding to the C2 domain of anti-C2 domain antibodies from pooled plasma samples. Nine peptides were thus selected and tested again in individual plasma samples. Our results support the view that C2 domain epitopes are organized as an epitopic mosaic distributed around the molecule, showed that each patient displayed a specific anti-C2 epitopic profile, and confirmed the complexity and variability of the immune response against the C2 domain of FVIII. This ability to finely map epitopes could be further used to follow the antibody specificity modifications over time. [ABSTRACT FROM AUTHOR]

Chronic Immune Thrombocytopenia (cITP) is an acquired immune-mediated disease associated with a T-helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [ IL1B−31T/C, IL1RN variable number tandem repeats (VNTR), IL2−330T/G, and TNF−307G/A] as well as in genes that code Toll like receptors (TLR) ( TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg392stop) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 ( P = 0·001) and of the IL2−330 polymorphic allele G ( P = 0·004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)-1α and IL-1β were observed in cITP ( P < 10−3) and blood donor ( P = 0·04) carriers of the IL1RN*2. Also, the serum levels of IL-2 and γ-interferon (IFN-γ) were increased in cITP patients ( P < 10−3 and P = 0·04 respectively) and blood donors ( P < 10−3 and P = 0·03 respectively) harbouring the IL2−330G allele. Here we demonstrated that IL2−330 G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP. [ABSTRACT FROM AUTHOR]

Early chronic lymphocytic leukaemia (CLL) is an ideal disease for immunotherapy. We previously showed that SEMG 1 is a cancer-testis (CT) antigen in CLL. In this study, SEMG 1 was applied as the bait in a yeast two-hybrid system of a testicular cDNA library. Seven clones were isolated and Protamine (Prm) 1 was identified as a novel CT antigen in early CLL. PRM1 transcripts were detected in 11/41 (26·8%) patients. Prm 1 protein was also expressed but heterogeneously within individual patients. Of the 11 patients expressing Prm 1, four expressed Zap 70 protein and seven did not. These results, therefore, indicate that Prm 1 could potentially be a suitable target for the design of tumour vaccine for patients with early CLL, including for those with poor risk CLL. High titres of Prm 1 IgG antibodies could be detected in 20 of these 41 CLL patients but not in any of the 20 healthy donors ( P = 0·0001), suggesting the presence of Prm 1-reactive immune responses within the immune repertoire of patients with early CLL. Further work is warranted, especially in approaches to upregulate Prm 1 expression, and to determine the role of Prm 1 as an immunotherapeutic target for early CLL. [ABSTRACT FROM AUTHOR]

Mature B-cells can recognize microbial antigens via B-cell-receptor (BCR) in a specific way and via Toll-like receptors (TLR) in a costimulatory manner. A wealth of information is gathering on the possible role of antigenic stimulation in the natural history of Chronic Lymphocytic Leukaemia (CLL). However little is known regarding the repertoire and function of TLR in CLL cells. The TLR family includes 10 different transmembrane proteins devoted to recognize specific pathogen-associated molecular patterns and to alarm immunocompetent cells to trigger an immune response. Here, we studied fresh leukaemic cells for the expression pattern of TLR1 to TLR10, NOD1, NOD2 and SIGIRR (also known as TIR8). CLL cells were found to express several pattern recognition receptors including TLR1, TLR2, TLR6, TLR10, NOD1 and NOD2. The specific TLR expressed by CLL cells were functional. Leukaemic cells, upon stimulation with TLR1/2/6 ligands, such as bacterial lipopeptides, activated the nuclear factor-κB signalling pathway, expressed CD86 and CD25 activation molecules, and were protected from spontaneous apoptosis. These findings further support the hypothesis that CLL cells resemble antigen-activated B-cells and suggest a potential role of TLR in modulating CLL cell response in the context of specific antigen recognition. [ABSTRACT FROM AUTHOR]

CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti-tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25− T cells in a dose-dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down-regulation of the transcription factor forkhead box P3, glucocorticoid-induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor κB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25− T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft-versus-leukaemia effect but also the graft-versus-host-disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib. [ABSTRACT FROM AUTHOR]

Plasma microparticles (MPs, <1·5 μm) originate from platelet and cell membrane lipid rafts and possibly regulate inflammatory responses and thrombogenesis. These actions are mediated through their phospholipid-rich surfaces and associated cell-derived surface molecules. The ectonucleotidase CD39/ecto-nucleoside triphosphate diphosphohydrolase1 (E-NTPDase1) modulates purinergic signalling through pericellular ATP and ADP phosphohydrolysis and is localized within lipid rafts in the membranes of endothelial- and immune cells. This study aimed to determine whether CD39 associates with circulating MPs and might further impact phenotype and function. Plasma MPs were found to express CD39 and exhibited classic E-NTPDase ecto-enzymatic activity. Entpd1 ( Cd39) deletion in mice produced a pro-inflammatory phenotype associated with quantitative and qualitative differences in the MP populations, as determined by two dimensional-gel electrophoresis, western blot and flow cytometry. Entpd1-null MPs were also more abundant, had significantly higher proportions of platelet- and endothelial-derived elements and decreased levels of interleukin-10, tumour necrosis factor receptor 1 and matrix metalloproteinase 2. Consequently, Cd39-null MP augment endothelial activation, as determined by inflammatory cytokine release and upregulation of adhesion molecules in vitro. In conclusion, CD39 associates with circulating MP and may directly or indirectly confer functional properties. Our data also suggest a modulatory role for CD39 within MP in the exchange of regulatory signals between leucocytes and vascular cells. [ABSTRACT FROM AUTHOR]

The eradication of inhibitory antibodies in patients with haemophilia A can be accomplished by frequent administration of high or intermediate doses of factor VIII (FVIII), so-called immune tolerance induction (ITI). This study monitored the distribution of IgG subclasses of anti-FVIII antibodies during ITI. FVIII-specific antibodies of subclass IgG1 were detected in all inhibitor patients tested, anti-FVIII IgG4 in 16, IgG2 in 10 and IgG3 in one of 20 patients analysed. Levels of anti-FVIII IgG1 and IgG4 correlated well with inhibitor titres as measured by Bethesda assay. In low-titre inhibitor patients, anti-FVIII antibodies consisted primarily of subclass IgG1 whereas, anti-FVIII antibodies of subclass IgG4 were more prominent in patients with high titre inhibitors who needed prolonged treatment or who failed ITI. Longitudinal analysis of 14 patients undergoing ITI revealed that the relative contribution of IgG subclasses was constant for most of the patients analysed. In two patients, the relative contribution of IgG4 increased during ITI. Overall, our findings document the distribution and dynamics of anti-FVIII IgG subclasses during ITI. Future studies will need to address whether monitoring the relative contribution of anti-FVIII subclasses IgG1 and IgG4 may be useful for the identification of patients who are at risk of failing ITI. [ABSTRACT FROM AUTHOR]

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vβ) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vβ family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Haemolytic disease of the newborn (HDN) can be prevented by the passive administration of anti-D to the mother. The most accepted theory to describe this activity of anti-D is based upon its ability to clear opsonized erythrocytes before their recognition by the maternal immune system. We examined this hypothesis using a murine model of immunity to foreign erythrocytes. Whereas transfusion of foreign erythrocytes into mice induced immunoglobulin (Ig)M and IgG antibodies specific for the erythrocytes, these humoral immune responses were inhibited when the erythrocytes were opsonized with IgG. To specifically determine if immunological evasion occurs with these opsonized erythrocytes, we examined T-cell responses from these mice. An erythrocyte-specific T-cell response was clearly detected. We then tested whether phagocytosis of opsonized erythrocytes is sufficient to prevent the antibody response. We exposed mononuclear phagocytic cells to sheep red blood cells (SRBC) in vitro and then adoptively transferred the phagocytic cells to recipient mice; opsonized SRBC unexpectedly increased, rather than decreased, the antibody response. These data indicate that removal of opsonized erythrocytes by phagocytic cells does not prevent their immunological recognition and suggest that antigen clearance may not be the predominant mechanism of anti-erythrocyte action in downregulating the humoral immune response. [ABSTRACT FROM AUTHOR]

T-cell large granular lymphocyte leukaemia (T-LGL) is a chronic clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGL presents with cytopenias, often accompanied by autoimmune diseases, suggesting clonal transformation arising from an initially polyclonal immune response. Various immunogenetic predisposition factors, previously described for both immune-mediated bone marrow failure and autoimmune conditions, may promote T-LGL evolution and/or development of cytopenias. The association of T-LGL was analysed with a number of immunogenetic factors in 66 patients, including human leucocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genotype, KIR/KIR-L mismatch, CTLA-4 (+49 A/G), CD16− 158V/F, CD45 polymorphisms, cytokine single nucleotide polymorphisms including: TNF- α (−308 G/A), TGF- β 1 (codons 10 C/T, 25 G/C), IL-10 (−1082 G/A), IL-6 (−174 C/G), and IFN- γ (+874 T/A). A statistically significant increase in A/A genotype for TNF- α−308, IL-10–1082, and CTLA-4 +49 was observed in T-LGL patients compared with control, suggesting that the G allele serves a protective role in each case. No association was found between specific KIR/HLA profile and disease. KIR/KIR-L analysis revealed significant mismatches between KIR3DL2 and KIR2DS1 and their ligands HLA- A3/11 and HLA-C group 2 ( P = 0·03 and 0·01 respectively); the biological relevance of this finding is questionable. The significance of additional genetic polymorphisms and their clinical correlation to evolution of T-LGL requires future analysis. [ABSTRACT FROM AUTHOR]

Extranodal marginal zone B-cell lymphomas (EMZL) are thought to develop from reactive infiltrates that represent immune responses to external or auto-antigens. Except for gastric EMZL, the antigenic triggers of EMZL development are mostly unknown, although a subset of cutaneous EMZL have been associated with Borrelia burgdorferi infections. To further evaluate whether a common antigen may be promoting the development of cutaneous EMZL, the immunoglobulin heavy chain variable (VH) genes from eight USA cases were sequenced and analysed. All used VH3 family gene segments, with 2/8 using the same V3–30 segment, 2/8 using the closely related V3–30·3 or V3–33 segments, 6/8 containing mutations and 2/7 showing evidence of ongoing mutation. Many of the complimentarity-determining region 3s (CDR3s) also showed similarities in length and displayed conserved amino acid motifs in the non-templated areas between the diversity and joining segments. The use of similar VH gene segments and conserved CDR3 amino acid motifs suggests that some of these cutaneous EMZL may bind the same or similar antigen via their surface immunoglobulin receptor. Analysis of the somatic mutations present in many of the VH genes was also consistent with antigen directly stimulating the growth of cutaneous EMZL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy and, although current therapy is widely effective, relapse remains a significant clinical problem for which new treatment strategies are required. The ligation of Toll-like receptors (TLR) on antigen-presenting cells stimulates the generation of strong T-cell helper type 1 (Th1) adaptive immune responses. Although TLR9 ligation has been shown to enhance immunogenicity of a number of leukaemia cell types, there have been few reports of the effects mediated through other TLR. In this study we analysed both the expression of TLR by B-cell precursor ALL cell lines and the effects of individual TLR ligation on the ability of ALL cells to stimulate allogeneic T cells. While ligation of TLR2, TLR 7 and TLR9 led to detectable changes in ALL costimulatory molecule expression, only TLR2 and TLR9 stimulation influenced T-cell responses. The TLR2 ligand Pam3CysSerLys4 provoked the most significant changes in T-cell response, dramatically augmenting interferon- γ production. These results suggest that TLR ligands, in addition to TLR9 agonists, may provide a strategy to enhance the generation of anti-ALL immune activity by skewing responding T cells towards a Th1 response. [ABSTRACT FROM AUTHOR]

There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3′-untranslated region (AT)82 alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1·2–3·2, and OR = 1·6, 95% CI = 1·1–2·4 respectively]. CTLA4-318C:49A:(AT)82 was the most represented haplotype in the studied population and was associated with NHL ( P = 0·0029, OR = 1·76, 95% CI = 1·2–2·5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a‘common’ haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients. [ABSTRACT FROM AUTHOR]

The role of antigen-specific CD3+CD8+ cytotoxic T cells in the control of primary Epstein–Barr Virus (EBV) infection is well established. However, time is required for the antigen-specific immune response to develop and expand. In contrast, innate immune responses, such as natural killer (NK) cells, are considered vital early in the infection process. We analysed the scale, phenotype and function of the NK cell response during symptomatic primary EBV infection, infectious mononucleosis (IM) and showed that NK cell numbers were significantly elevated both at diagnosis of IM and in the first month following diagnosis. There were also significant changes in cell phenotype and function, an increase in the proportion of CD56bright cells at diagnosis, and freshly isolated cells showing an enhanced ability to kill EBV-infected cell lines. Moreover, in our cohort of IM patients higher NK cell counts were associated with significantly lower viral load in peripheral blood. Our results suggest NK cells have an important role in the control of primary EBV infection by eliminating infected B cells and augmenting the antigen-specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a clinical outcome. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that granulocyte colony-stimulating factor (G-CSF) stimulated the production of epithelial-cell-derived-neutrophil attractant-78 (ENA-78) by neutrophils and that ENA-78 might promote the accumulation of neutrophils that had migrated from the intravascular space into inflammatory tissues. In this study, we examined whether other chemokines could be secreted by neutrophils that had accumulated after migrating from the intravascular space into the inflammatory tissues. We demonstrated that adhesion to laminin contained in the basement membrane and Matrigel, which is an artificial basement membrane model, induced macrophage inflammatory protein-1β (MIP-1β) in neutrophils and that MIP-1β secreted by neutrophils induced the chemotaxis of dendritic cells. These findings suggest that neutrophils transmigrating through the basement membrane are stimulated to secrete MIP-1β by the basement membrane, inducing the transmigration of dendritic cells from the intravascular space into inflammatory tissues. We propose that neutrophils intervene between innate immune response and specific immune response by secreting MIP-1β during the transmigration through the basement membrane. [ABSTRACT FROM AUTHOR]

Human peripheral blood γ δ T cells (V γ9+ V δ2+) can be selectively expanded in vivo by the systemic administration of aminobisphosphonates without prior antigen priming. To assess the potential of human γ δ T cells to serve as effector cells of specific anti-tumour immunity, we expanded peripheral blood-derived γ δ T cells and transduced them with recombinant retrovirus encoding GD2- or CD19-specific chimaeric receptors. Flow cytometric analysis of T cells from four individual donors cultured in the presence of zoledronate at day 14 of culture showed selective enrichment of the γ δ T cell population (V γ9+ V δ2+ CD3+ CD4− CD8−) to 73–96% of total CD3+ T cells. Retroviral gene transfer resulted in chimaeric receptor surface expression in 73 ± 12% of the population. Transduced γ δ T cells efficiently recognized antigen-expressing tumour cell targets, as demonstrated by target-specific upregulation of CD69 and secretion of interferon- α. Moreover, transduced γ δ T cells efficiently and specifically lysed the antigen-expressing tumour targets. They could be efficiently expanded in vitro and maintained in culture for prolonged periods. Zoledronate-activated human γ δ T cells expressing chimaeric receptors may thus serve as potent and specific anti-tumour effector cells. Their responsiveness to stimulation with aminobisphosphonates may enable the selective re-expansion of adoptively transferred T cells in vivo, permitting long lasting anti-tumour immune control. [ABSTRACT FROM AUTHOR]

The effects of donor T cells, or their CD8+ subset, on engraftment and tolerance induction in fetal transplantation were evaluated using an F1-into-parent mouse-model that does not permit a graft- versus-host effect. Gestational day 13 C57BL/6 (H-2Kb) fetuses were transplanted with B6D2F1 (H-2Kb/d) light density bone marrow cells (LDBMC) containing 1–2% T cells, T-cell depleted bone marrow cells (TDBMC, <0·1% T cells), or TDBMC with enriched CD8+ T cells (CD8). Chimaerism levels in the peripheral blood, spleen and bone marrow were usually below 0·2% in all groups, indicating that T cells do not improve engraftment without a graft- versus-host effect. A significant, but transient, wave of donor cells was seen in the peripheral blood at 1 month of age in the CD8 and LDBMC groups. Relatively high levels of chimaerism (<17%) were sometimes detected in the peritoneal cavities of recipients. T-cell tolerance specific to donor cells was evaluated in mixed lymphocyte cultures. The CD8 and LDBMC groups had significantly lower T-cell responses than untransplanted controls. These findings indicate that in utero transplantation of haploidentical donor CD8+ or CD3+ cells can help to lessen the immune response of host T cells towards donor cells. The persistence of donor cells in the peritoneal cavity also correlated with tolerance induction. [ABSTRACT FROM AUTHOR]

The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor β1 (TGF β1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF β1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- γ neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123−) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- γ to future immunotherapy trials involving these patients should be considered. [ABSTRACT FROM AUTHOR]