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Abstract Aggressive B-cell non-Hodgkin lymphomas (NHL) in children, adolescents, and young adults (CAYA) include Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and a subset of high-grade tumors with features intermediate between these entities whose genetic and molecular profiles have not been completely elucidated. In this study, we have characterized 37 aggressive B-NHL in CAYA, 33 with high-grade morphology, and 4 DLBCL with MYC rearrangement (MYC-R), using targeted next-generation sequencing and the aggressive lymphoma gene expression germinal center B-cell-like (GCB), activated B-cell-like (ABC), and dark zone signatures (DZsig). Twenty-two tumors had MYC-R without BCL2 breaks, and two MYC-non-R cases had BCL6 translocations. MYC-R cases, including DLBCL, carried BL-related mutations and copy number alterations. Conversely, MYC-non-R lymphomas had alterations in the B-cell receptor signaling/NF-κB pathway (71%). DZsig was expressed in 12/13 of MYC-R tumors but only in 2/10 of MYC-non-R GCB tumors (P

Purpose: The optimal management of stage II follicular lymphoma (FL) is unclear. Radiation therapy (RT) alone has been the gold standard treatment, but a proportion of patients relapse. We sought to characterize outcomes and prognostic factors for stage II FL treated with RT alone to identify a high-risk subgroup of patients who may benefit from treatment intensification. Methods: This was a population-based, province-wide, retrospective study. Included patients had grade 1–3A, non-mesenteric, stage IIA or IIAE FL diagnosed between 1986 and 2016 and treated with curative-intent (≥20 Gy) RT alone. Results: 102 patients were included. Median follow-up was 10.4 years (range, 0.3–22.3). Median age was 59 years (range, 33–86). Median greatest disease diameter was 3.6 cm (range, 1.5–11.5). Freedom from progression (FFP) was 60.3% at 5 years and 40.7% at 10 years. Overall survival (OS) was 89.2% at 5 years and 81.8% at 10 years. Greatest disease diameter of >3.6 cm was associated with inferior FFP (10-year FFP 34% vs. 47%, p = 0.013) on univariable analysis and inferior FFP (hazard ratio [HR] 1.87, p = 0.019) and inferior OS (HR 2.12, p = 0.027) on multivariable analysis (MVA). Older age was associated with inferior OS (HR 1.08, unit = 1 year, p 3.6 cm was associated with inferior FFP and OS, representing a novel prognostic indicator in this population that may help in the decision-making process on whether to complement RT with systemic therapy.

Abstract Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.

Over the past few years, we have seen an increased need to analyze the dynamically changing behaviors of economic and financial time series. These needs have led to significant demand for methods that denoise non-stationary time series across time and for specific investment horizons (scales) and localized windows (blocks) of time. Wavelets have long been known to decompose non-stationary time series into their different components or scale pieces. Recent methods satisfying this demand first decompose the non-stationary time series using wavelet techniques and then apply a thresholding method to separate and capture the signal and noise components of the series. Traditionally, wavelet thresholding methods rely on the discrete wavelet transform (DWT), which is a static thresholding technique that may not capture the time series of the estimated variance in the additive noise process. We introduce a novel continuous wavelet transform (CWT) dynamically optimized multivariate thresholding method (WaveL2E). Applying this method, we are simultaneously able to separate and capture the signal and noise components while estimating the dynamic noise variance. Our method shows improved results when compared to well-known methods, especially for high-frequency signal-rich time series, typically observed in finance.

Healthy individuals are generally immunologically tolerant to proteins derived from one’s self (termed self proteins). However, patients with monogenic clotting disorders, like hemophilia A (HemA), lack central tolerance to the absent self protein. Thus, when exposed to replacement therapy, such as procoagulant factor VIII, they may mount an immune response against the very self protein that is missing. In the current issue of the JCI, Becker-Gotot, Meissner, et al. present data on a possible mechanism for tolerance to factor VIII in healthy individuals and the immune response in patients, involving a role of PD-1 and T regulatory cells. The findings suggest that treatment with PD-1– and PD-1L–specific reagents may induce tolerance in patients with autoimmune disease, especially those with HemA who also possess inhibiting antibodies.

Abstract Background SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. Methods A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant’s cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. Discussion This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates.

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell–mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

Regulatory T cells (Tregs) play a role in the induction and maintenance of tolerance, as well as in modulating aberrant immune responses. While expanded Tregs have been used in clinical trials, they are polyclonal and the frequency of specific Tregs is very low. To overcome this issue, we have endeavored to “specify” Tregs by engineering them to express receptors that can recognize a given antigen and applied this protocol in autoimmunity, hemophilia and allergy. Thus, we have used retroviral transduction of a specific T cell receptor, single-chain variable fragments (Fvs), or antigen domains in Tregs to achieve this goal. This review summarizes our steps to achieve the ultimate goal of modulating human diseases.

Abstract: The objective of this study was to evaluate the distribution and prognostic impact of a broad range of molecular attributes in a large cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) by using tissue microarray. Patients diagnosed with PCNSL were initially identified in the BC Cancer Lymphoid Cancer clinical and pathology databases. Tissue microarrays were constructed by using archival formalin-fixed paraffin-embedded diagnostic biopsy tissue. Immunohistochemistry and fluorescent in situ hybridization studies were performed. A total of 115 patients with PCNSL with diffuse large B-cell lymphoma (DLBCL) histology were identified. The majority of cases (≥75%) had a non–germinal center B-cell phenotype according to immunohistochemistry algorithms, but cell of origin did not affect progression-free or overall survival. MYC (40%), BCL2 (75%), and programmed death-ligand 1 (29%) protein expression were common, but their corresponding gene rearrangements were rare (≤1% each), suggesting that alternate mechanisms were driving expression. There were no dual rearrangements involving MYC and BCL2. Only 22% of cases had membranous expression of major histocompatibility complex class II, suggesting a mechanism for escape from immune surveillance. Epstein-Barr virus–encoded RNA was positive in 1 immunocompetent patient. BCL6 protein expression (77%) and BCL6 rearrangements (31%) were frequent; the latter was the only factor associated with a poor prognosis in the overall cohort and in the subgroup of 52 patients treated with high-dose methotrexate–based regimens. This large population-based study shows that prominent molecular features of PCNSL are unique and different from those of systemic DLBCL. These results may better inform drug development in PCNSL.

Chimeric antigen receptor (CAR) transduced T cells have significantly improved cancer immunotherapy. Similarly, engineering regulatory T cells (Treg) with specific receptors to endow specificity and increase efficacy of Tregs holds great promise for therapy of a variety of adverse immune responses. In this review, we focus on our approaches using retroviral transduction of specific T-cell receptors, single chain variable fragments (scFv) or antigen in models of monogenic diseases, autoimmunity and allergy. The advantages of each of these for different targets diseases are discussed as well as their potential for clinical translation.

Abstract: In advanced-stage diffuse large B-cell lymphoma (DLBCL), the presence of an activated B-cell phenotype or a non–germinal center (GCB) phenotype, coexpression of MYC and BCL2 by immunohistochemistry, and the cooccurrence of MYC and BCL2 or BCL6 rearrangements are associated with inferior outcomes. It is unclear whether these variables remain prognostic in stage I/II patients. In this retrospective study, we evaluated the prognostic impact of cell of origin (COO), as well as dual-expressor (DE) status and molecular double-hit (DH) status, in stage I/II DLBCL by positron emission tomography with computed tomography (PET-CT). A total of 211 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimens, with or without radiotherapy, was included. The median follow-up in the entire cohort was 4 years (range, 0.4-9.4), with estimated 4-year progression-free survival (PFS) and overall survival (OS) rates of 85% (95% confidence interval [CI], 79-89) and 88% (95% CI, 83-92), respectively. By univariable analysis, DE (PFS: hazard ratio [HR], 1.27; 95% CI, 0.58-2.81, P = .55 and OS: HR, 1.40; 95% CI, 0.60-3.30; P = .44), DH (PFS: HR, 1.21; 95% CI, 0.27-5.31; P = .80 and OS: HR, 0.61; 95% CI, 0.08-4.73; P = .64), and non-GCB status (PFS: HR, 1.59; 95% CI, 0.83-3.03; P = .16 and OS: HR, 1.80; 95% CI, 0.89-3.67; P = .10) were associated with poorer outcomes. In patients with PET-CT–defined stage I/II DLBCL treated with R-CHOP–like therapy, with or without radiation, COO and DE and DH status were not significantly associated with inferior PFS or OS.

Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large-cell morphology and terminal B-cell differentiation. The differential diagnosis from Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging because of the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated 34 cases of PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma-related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2- q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, Epstein-Barr virus (EBV)-negative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBVpositive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors in relation to EBV infection.

Anti-drug antibody formation poses tremendous obstacles for optimal treatment of hemophilia A (HA). In this study, we sought to utilize chimeric receptor-modified natural regulatory T cells (Tregs) to target FVIII-specific memory B cells, which are responsible for persistent anti-FVIII neutralizing antibodies (inhibitors) in HA patients. Thus, CD4+CD25hiCD304+ natural Tregs were FACS sorted from naïve C57BL/6 mice and retrovirally transduced to express a chimeric B-cell antibody receptor (BAR) containing the immunodominant A2 domain of FVIII. Plasmablast-depleted (CD138neg) splenocytes from FVIII immunized FVIII-knockout HA mice served as the source for FVIII-specific memory B cells, which were specifically stimulated in vitro with FVIII and enumerated in a B-cell ELISPOT assays. Adding A2-BAR Tregs (1 per 150 splenocytes), but not conventional T cells, to the CD138– splenocytes significantly suppressed the formation of anti-FVIII antibody secreting cells (ASC), compared to the non-relevant OVA-BAR Tregs control group. The observation that A2-BAR Tregs can suppress the response to FVIII suggests that bystander suppression can occur in the local milieu in this system. Transwell experiments confirmed that the suppression was contact-dependent. Moreover, even in the presence of antibodies to FVIII (so-called inhibitors), similarly prepared CD4+CD25hiCD127low A2-BAR human natural Tregs completely suppressed polyclonal anti-FVIII ASC formation. In conclusion, we demonstrated in vitro that FVIII domain-expressing BAR Tregs could efficiently target and suppress FVIII-specific memory B cells.

The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is a major complication of hemophilia A treatment. The sole clinical therapy to restore FVIII tolerance in patients with inhibitors remains immune tolerance induction (ITI) which is expensive, difficult to administer and not always successful. Although not fully understood, the mechanism of ITI is thought to rely on inhibition of FVIII-specific B cells (1). Its efficacy might therefore be improved through more aggressive B cell suppression. FcγRIIB is an inhibitory Fc receptor that down-regulates B cell signaling when cross-linked with the B cell receptor (BCR). We sought to investigate if recombinant FVIII Fc (rFVIIIFc), an Fc fusion molecule composed of FVIII and the Fc region of immunoglobulin G1 (IgG1) (2), is able to inhibit B cell activation more readily than FVIII. rFVIIIFc was able to bind FVIII-exposed and naïve B cells from hemophilia A mice as well as a FVIII-specific murine B cell hybridoma line (413 cells). An anti-FcγRIIB antibody and FVIII inhibited binding, suggesting that rFVIIIFc is able to interact with both FcγRIIB and the BCR. Furthermore, incubation of B cells from FVIII-exposed mice and 413 cells with rFVIIIFc resulted in increased phosphorylation of SH-2 containing inositol 5-phosphatase (SHIP) when compared to FVIII. B cells from FVIII-exposed hemophilia A mice also exhibited decreased extracellular signal-regulated kinase (ERK) phosphorylation when exposed to rFVIIIFc. These differences were absent in B cells from naïve, non-FVIII exposed hemophilic mice suggesting an antigen-dependent effect. Finally, rFVIIIFc was able to inhibit B cell calcium flux induced by anti-Ig F(ab)2. Our results therefore indicate that rFVIIIFc is able to crosslink FcγRIIB and the BCR of FVIII-specific B cells, causing inhibitory signaling in these cells.

Therapeutic treatment of bleeds with FVIII can lead to an antibody response that effectively inhibits its function. Herein, we review the factors that contribute to this immunogenicity and possible ways to overcome it.

Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as “inhibitors,” which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was “Immune Tolerance Induction,” consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ~30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to “bypass” the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

The driver mutations for the two main molecular subgroups of diffuse large B-cell lymphoma (DLBCL) are poorly defined. Here, an integrative genomics analysis identifies 3′ UTR NFKBIZ mutations within the activated B-cell DLBCL subgroup and small FCGR2B amplifications in the germinal centre B-cell DLBCL subgroup.

In diffuse large B-cell lymphoma (DLBCL) increased epigenetic heterogeneity in the form of cytosine methylation is known to link to a poor clinical outcome. Here, the authors show that AICDA, an enzyme required for DLBCL pathogenesis, increases cytosine methylation heterogeneity.

University ranking is a popular yet controversial endeavor. Most rankings are based on both public data, such as student test scores and retention rates, and proprietary data, such as school reputation as perceived by high school counselors and academic peers. The weights applied to these characteristics to compute the rankings are often determined in a subjective fashion. Of significant importance in the academic field, the Carnegie Classification was developed by the Carnegie Foundation for the Advancement of Teaching. It has been updated approximately every 5 years since 1973, most recently in February 2016. Based on bivariate scores, Carnegie assigns one of three classes (R1/R2/R3) to doctorate-granting universities according to their level of research activity. The Carnegie methodology uses only publicly available data and determines weights via principal component analysis. In this article, we review Carnegie’s stated goals and the extent to which their methodology achieves those goals. In particular, we examine Carnegie’s separation of aggregate and per capita (per tenured/tenure-track faculty member) variables and its use of two separate principal component analyses on each; the resulting bivariate scores are very highly correlated. We propose and evaluate two alternatives and provide a graphical tool for evaluating and comparing the three scenarios.

As modern data analysis pushes the boundaries of classical statistics, it is timely to reexamine alternate approaches to dealing with outliers in multiple regression. As sample sizes and the number of predictors increase, interactive methodology becomes less effective. Likewise, with limited understanding of the underlying contamination process, diagnostics are likely to fail as well. In this article, we advocate for a non-likelihood procedure that attempts to quantify the fraction of bad data as a part of the estimation step. These ideas also allow for the selection of important predictors under some assumptions. As there are many robust algorithms available, running several and looking for interesting differences is a sensible strategy for understanding the nature of the outliers.

The objective of this study was to create a bioclinical model, based on clinical and molecular predictors of event-free and overall survival for relapsed/refractory diffuse large B-cell lymphoma patients treated on the Canadian Cancer Trials Group (CCTG) LY12 prospective study. In 91 cases, sufficient histologic material was available to create tissue microarrays and perform immunohistochemistry staining for CD10, BCL6, MUM1/IRF4, FOXP1, LMO2, BCL2, MYC, P53 and phosphoSTAT3 (pySTAT3) expression. Sixty-seven cases had material sufficient for fluorescent in situ hybridization (FISH) for MYC and BCL2. In addition, 97 formalin-fixed, paraffin-embedded tissue samples underwent digital gene expression profiling (GEP) to evaluate BCL2, MYC, P53, and STAT3 expression, and to determine cell-of-origin (COO) using the Lymph2Cx assay. No method of determining COO predicted event-free survival (EFS) or overall survival (OS). Factors independently associated with survival outcomes in multivariate analysis included primary refractory disease, elevated serum lactate dehydrogenase (LDH) at relapse, and MYC or BCL2 protein or gene expression. A bioclinical score using these four factors predicted outcome with 3-year EFS for cases with 0–1 vs. 2–4 factors of 55% vs. 16% (P

Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive non-Hodgkin’s lymphoma, predominantly affecting young patients. We analyzed 45 primary PMBCL tumor biopsies and 3 PMBCL-derived cell lines for the presence of genetic alterations involving the major histocompatibility complex (MHC) class II transactivator CIITA and found frequent aberrations consisting of structural genomic rearrangements, missense, nonsense, and frame-shift mutations (53% of primary tumor biopsies and all cell lines). We also detected intron 1 mutations in 47% of the cases, and detailed sequence analysis strongly suggests AID-mediated aberrant somatic hypermutation as the mutational mechanism. Furthermore, we demonstrate that genomic lesions in CIITA result in decreased protein expression and reduction of MHC class II surface expression, creating an immune privilege phenotype in PMBCL. In summary, we establish CIITA alterations as a common mechanism of immune escape through reduction of MHC class II expression in PMBCL, with potential implications for future treatments targeting microenvironment-related biology.

Recent efforts have concentrated on approaches to expand and “specify” human regulatory T cells (Tregs) and to apply them to modulate adverse immune responses in autoimmunity and hemophilia. We have used retroviral transduction of specific T-cell receptor, single chain Fv, or antigen domains in Tregs to achieve this goal. Each of these approaches have advantages and disadvantages. Results with these engineered T cells and evolution of the research developments and paths that led to the development of specific regulatory approaches for tolerance are summarized.

Human regulatory CD4+ T cells (Tregs) are potent immunosuppressive lymphocytes responsible for immune tolerance and homeostasis. Since the seminal reports identifying Tregs, vast research has been channeled into understanding their genesis, signature molecular markers, mechanisms of suppression, and role in disease. This research has opened the doors for Tregs as a potential therapeutic for diseases and disorders such as multiple sclerosis, type I diabetes, transplantation, and immune responses to protein therapeutics, like factor VIII. Seminal clinical trials have used polyclonal Tregs, but the frequency of antigen-specific Tregs among polyclonal populations is low, and polyclonal Tregs may risk non-specific immunosuppression. Antigen-specific Treg therapy, which uses genetically modified Tregs expressing receptors specific for target antigens, greatly mitigates this risk. Building on the principles of T-cell receptor cloning, chimeric antigen receptors (CARs), and a novel CAR derivative, called B-cell antibody receptors, our lab has developed different types of antigen-specific Tregs. This review discusses the current research and optimization of gene-modified antigen-specific human Tregs in our lab in several disease models. The preparations and considerations for clinical use of such Tregs also are discussed.

At the turn of the twentieth century, Western missionaries and mission organizations sought to develop financial strategies that would facilitate the further expansion of the Western mission enterprise. Three such strategies emerged: an increasingly sophisticated, corporatized approach to fundraising by mission boards; faith missions that shifted the economic risks associated with fundraising from mission agencies to missionaries; and self-supporting missions that cultivated economic funding available in the mission field. Each of these strategies had different implications for power configurations in the mission enterprise and allowed the values and views of different groups to prevail. The board approach empowered mission executives and large donors. The faith mission approach empowered missionaries and supporters with a conservative theology. The self-supporting mission approach made missionaries arbiters among a variety of competing interests. This economic approach to the study of mission provides new insights into the complex and contested power arrangements involved in Western foreign mission that extend beyond those gained from traditional political and cultural analyses.

HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+ T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells’ (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.

The induction of immunologic tolerance is an important clinical goal in autoimmunity. CD4+ regulatory T (Treg) cells, defined by the expression of the transcription factor forkhead box P3 (FoxP3), play a central role in the control of autoimmune responses. Quantitative and qualitative defects of Tregs have been postulated to contribute to failed immune regulation in multiple sclerosis (MS) and other autoimmune diseases. This paper highlights the potential uses of T regulatory cell epitopes (Tregitopes), natural Treg epitopes found to be contained in human immunoglobulins, as immunomodulating agents in MS. Tregitopes expand Treg cells and induce “adaptive Tregs” resulting in immunosuppression and, therefore, are being considered as a potential therapy for autoimmune diseases. We will compare Tregitopes versus intravenous immunoglobulin (IVIg) in the treatment of EAE with emphasis on the potential applications of Tregitope for the treatment of MS.