T cell targeted immunotherapy for autoimmune disease

Much emphasis has been placed on the so-called “biologics” in the treatment of immune disorders within the last few years. Here we discuss the expanding horizon of potential strategies for immunotherapies targeting T lymphocytes as key effectors and regulators of autoimmunity. We review emerging reagents in a variety of animal models and human disorders that may offer new therapeutic options in current or modified iterations.     

T细胞疫苗抑制自身免疫性甲状腺炎的发生

目的　研究T细胞疫苗 (TCV)在小鼠实验性自身免疫性甲状腺炎 (EAT)发生中的阻断作用及可能机制。方法　磁珠分离CD4 T细胞 ,体外活化 ,戊二醛处理获得T细胞疫苗 ,体内接种EAT小鼠。通过EAT评价、细胞因子测定及细胞增殖试验了解TCV对EAT的阻断作用 ;流式细胞术测定小鼠CD4 CD2 5 T细胞百分率。结果　TCV接种后小鼠体内自身抗体水平明显下降 ,甲状腺无明显病理变化 ,IL 2和IFN γ水平以及Tg刺激的淋巴细胞增殖能力均显著降低 ,同时CD4 CD2 5 T细胞百分率较EAT组有明显增高。结论　TCV接种能明显抑制小鼠EAT的发生 ,可能与机体内CD4 CD2 5 Treg细胞的增加有关     

T cell vaccination: clinical application in autoimmune diseases

 T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. We review here the recent application of T cell vaccination in patients with MS to deplete circulating MBP-reactive T cells. The results of our phase I clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderately lower rate of clinical exacerbation, disability score, and brain lesions (measured by magnetic resonance imaging) in vaccinated patients than in matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical administration in other human autoimmune diseases. This review discusses the immune regulation and therapeutic administration of T cell vaccination in human autoimmune diseases, exemplified by our recent T cell vaccination trial in MS. Received: 14 March 1996 / Accepted: 18 July 1996     

T细胞疫苗、肽疫苗免疫干预自身免疫病的进展

自身反应性T细胞在体内的免疫调节作用主要涉及独特型-抗独特型调节网络。病理性自身反应性T细胞是多发性硬化、类风湿性关节炎等自身免疫病的主要致病原因。本文综述利用这一调节机制治疗自身免疫病的T细胞疫苗和肽疫苗的研究现状和前景。     

Progress in hematopoietic stem cell transplantation for autoimmune diseases

An international co-ordinated Phase I/II program commenced 8 years ago to study the role of profound immunoablation with hematopoietic stem cell transplantation in the treatment of severe, refractory autoimmune disease. Almost 700 patients have been treated for a variety of autoimmune diseases, mostly multiple sclerosis, systemic sclerosis, also referred to as scleroderma, systemic lupus erythematosis, rheumatoid arthritis and juvenile idiopathic arthritis. An overall treatment-related mortality of 7% was observed, with significant differences between diseases; 11% in systemic lupus erythematosis and only one patient with rheumatoid arthritis. Although outcomes are disparate in different diseases, there were significant durable, clinically useful remissions, relapses, and nonresponders in all groups. Although different protocols were employed, a clear advantage from the more intensive myeloablative regimens was not observed, although an increased toxicity did occur. The Phase I/II data was exploited in designing the Phase III randomized, comparative trials that are running in systemic sclerosis, multiple sclerosis and rheumatoid arthritis in Europe, and at the advanced planning stage in systemic sclerosis, multiple sclerosis and systemic lupus erythematosis in the USA. In parallel, a basic science program is proceeding with the prospective studies to improve understanding of the mechanisms of autoimmune disease activity and remission.     

Activation of a myelin basic protein-specific human T cell clone by antigen-presenting cells from rhesus monkeys

This study addresses the capacity of peripheral blood mononuclearcells (PBMC) from rhesus monkeys (Macaca mulatta) to presentmyelin basic protein (MBP), a candidate auto-antigen for multiplesclerosis, to MBP-speclfic human CD4⁺ T cell clones. MHC-restrictlonof the human T cell clones was determined with HLA-DR-transfectedL cells, and epitope specificity was established with a panelof overlapping 20-mer peptides. The MHC-DR region of the rhesusmonkeys (Mamu) was characterized serologlcally and by sequenceanalysis. We identified one CD4⁺ HLADRB1*0301-restrlcted T_h1-llkehuman T cell clone (ES-BP8) that was activated to proliferationwith human or rhesus monkey MBP, or peptide MBP 29–48presented by PBMC from six different rhesus monkeys expressingthe Mamu-DRB1*0305 or -DRB1*0306 alleles. After transformationto continuous growth with Herpesvirus salmiri, the T cell clonecould still be stimulated by antigen (Ag) and Ag-presentlngcells (APC) from monkeys. Two other T cell clones with the sameHLA-restriction and the same peptide-specificity did not respondto MBP presented by these rhesus monkeys. The exon 2 sequencesHLA-DRB1*0301, Mamu-DRBV^*0305 and -DRB 1* 0306 differ at positions32, 47, 67, 73 and 86. These amino acid differences are notcritical for the binding of MBP 29–48 and do not abrogate-recognitionby the clone ES-BP8, but interfere with the recognition of thetwo other HLA-DRB1^*0301-restricted T cell clones. In conclusion,studying Ag-presentation from rhesus monkey may provide furtherinsight Into the Interaction of antigenic peptide, TCR and MHC.Furthermore, these results could form a useful basis for theIn vivo transfer of human auto-Ag-specific T cells into rhesusmonkey recipients.     

Is there a role for mesenchymal stem cells in autoimmune diseases?

Recent reports have highlighted that adult stem cells are granted with yet poorly understood properties other than multipotentiality. In particular, mesenchymal stem cells (MSCs) represent a subset of adult stromal cells that can down-regulate several functions of the immune cells. In addition, MSCs may promote survival of damaged cells and tissues through paracrine mechanisms, possibly under the guidance of environmental cues. Thus, MSCs clinical application in autoimmune diseases seems an appealing opportunity and preclinical results in different experimental models of autoimmunity further support this strategy. Despite the absolute need for caution related to several clinical and technical issues, MSCs are now on the edge of a new era of clinical applications.     

Humanized animal models for autoimmune diseases

The development of transgenic mice expressing human DR and DQ major histocompatibility complex (MHC) class II molecules has been of value in studying the immunopathology of human MHC class II-associated autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus and celiac disease. Such mice have been used to identify the target antigens that are involved in the initiation of these diseases. Many of the mice develop aspects of the human diseases, either spontaneously or following immunization with the relevant antigen, thus providing an in vivo disease model, which may be used as a tool for further understanding the disease mechanisms and testing novel immunotherapies.     

T细胞受体基因转染过继性免疫治疗的研究进展

利用T细胞进行过继性免疫治疗是治疗病毒感染性疾病和肿瘤的理想方法,但是用于治疗的T细胞的特异性、亲和性和数量等限制了其应用,如何获得特异、高效、一定数量的T细胞是目前亟待解决的问题。采用TCR基因转染的方法,将特异性高亲和力TCR转移到受体的T细胞中,可以特异性杀伤受体体内的肿瘤细胞。     

T cell vaccination therapy in an induced model of anti-RNP autoimmune glomerulonephritis

To establish the relevance of targeting disease-associated T cells in anti-RNP-associated glomerulonephritis, mice developing nephritis following immunization with U1-70-kd small nuclear ribonucleoprotein (snRNP) were treated with a single dose of irradiated antigen-selected T cell vaccine. T cell receptor usage in nephritic kidneys revealed oligoclonal use of T Cell Receptor V Beta (TRBV) genes as previously found in spleens and lungs of immunized mice with pulmonary disease. The CDR3 regions from T cell isolates showed sequence homology to those in humans with anti-RNP autoimmunity. Following T cell vaccination, urinalysis returned to normal in 5/7 treated mice (71% response rate) whereas all mock-treated mice continued to have an active urinary sediment (Fisher's Exact p = 0.02). An oligoclonal population of T cells homologous to those identified in humans with anti-RNP autoimmunity is implicated in disease pathogenesis, and T cell vaccination is associated with a high rate of clinical improvement in established nephritis.     

Peptide T does not ameliorate experimental autoimmune encephalomyelitis (EAE) in Lewis rats

Peptide T has been shown to inhibit T cell activation and cytokine production and function. Moreover, it has been reported to be a safe treatment in humans. We have studied the ability of peptide T to prevent or ameliorate EAE in Lewis rats. Peptide T was administered subcutaneously at different doses and phases of the disease according to several treatment protocols, but we could not observe a consistent effect of peptide T ameliorating the disease. Lymph node cell proliferation and IL-4 and interferon-gamma production were also studied. We conclude that peptide T neither prevents nor ameliorates EAE in Lewis rats.     

T细胞免疫治疗实体肿瘤的临床试验疗效分析

过继性T细胞治疗(adoptive cell transfer therapy,ACT)是以肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)、基因工程编辑的T细胞受体T细胞(T cell receptor engineered T cells,TCR-T)和嵌合抗原受体T细胞(ch...     

Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Adoptive T cell-based immunotherapies can mediate complete and durable regressions in patients with advanced cancer, but current response rates remain inadequate. Maneuvers to improve the fitness and antitumor efficacy of transferred T cells have been under extensive exploration in the field. Small non-coding microRNAs have emerged as critical modulators of immune system homeostasis and T cell immunity. Here, we summarize recent advances in our understanding of the role of microRNAs in regulating T cell activation, differentiation, and function. We also discuss how microRNA therapeutics could be employed to fine-tune T cell receptor signaling and enhance T cell persistence and effector functions, paving the way for the next generation of adoptive immunotherapies.     

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self‐antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4⁺ T cells that secrete interleukin (IL)‐17, termed Th17, but also IL‐17‐secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL‐17‐producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8⁺ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.     

Analysis of proteolipid protein (PLP)-specific T cells in multiple sclerosis: identification of PLP 95 116 as an HLA-DR2,w15-associated determinant

Multiple sclerosis (MS) is a putative autoimmune disease thatis linked with HLA-DR2,w15. Proteollpid protein (PLP) is a candidateautoantigen in MS, but the disease-associated epitopes havenot been determined. Using overlapplng and non-overlapping PLPpeptides, we have studied the T cell response to the major hydrophllicdomain PLP 85–159 in the peripheral blood of MS and healthysubjects (HS). Short-term T cell lines (TCL) were selected againsteach peptide using microwell plates and the frequency of peptide-specificTCL was estimated. PLP 95–116-specific TCL were most efficientlygenerated and the frequency was significantly higher in MS comparedwith HS (P <0.05). When compared between DR2,w15⁺ and DR2,w15^–MS, TCL frequency to PLP 95–116 was significantly higherin DR2,w15⁺ MS (P<0.005) and TCL reactive to the overlappingpeptide 105–124 were also increased in DR2,w15⁺ MS (P<0.025). Using DR gene-transfected L cells, we could show thatthe DRB1^*1501 product of the DR2 haplotype presents PLP 95–116to TCL selected against the pepide. These results imply thatPLP 95–116 represents a major epitope for the DR2,w15⁺MS.     

Harnessing proteases for T regulatory cell immunotherapy

The immune system is tightly regulated by a subset of T cells defined as regulatory T cells (Tregs). Tregs maintain immune homeostasis by restraining unwarranted immune cell activation and effector function. Here, we discuss an important but underappreciated role of proteases in controlling Treg function. Proteases regulate a number of vital processes that determine T cell immune responses and some of them such as furin, ADAM (through regulating LAG receptor), MALT, and asparaginyl endopeptidase are implicated in Treg immunobiology. Targeted protease inhibition, using either small molecule inhibitors or gene deficient mice has demonstrated their specificity in modulating Treg function in experimental murine models. These data further highlight the ability of proteases to specifically regulate Tregs but no other T effector lineages. Taken together, it is apparent that incorporating proteases as targets within Treg cell engineering protocols may enable generation of robust Treg cellular therapeutics. These engineered Tregs may possess enhanced regulatory function along with resistance to lineage deviation in inflammatory disease such as colitis and graft versus host disease. Within this review, we summarize research on the role of proteases in regulating Treg function and discuss the translational potential of harnessing Treg function by targeting protease driven regulatory pathways.     

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (T_FH) cells, rather than type 2 T-helper (T_H2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (T_FR) cells, a specialized subset of regulatory T (T_REG) cells resident in B-cell follicles, restricts T_FH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5⁺ T_FH cells, not CXCR5⁻ conventional T_H2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5⁺ T_FR cell deletion. Upregulation of T_FH cell activities, including a skewing toward type 2 T_FH (T_FH2) and IL-13 producing T_FH (T_FH13) phenotypes, and defects in T_FR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between T_FH and T_FR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of T_FH and T_FR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.     

T-cell receptor- and anti-inflammatory gene-modulated T cells as therapy for autoimmune disease

Antigen-specific immunotherapy is a future therapy that could achieve high efficacy with limited adverse effects. Although T cells are essential components in antigen-specific immunity, we do not have a practical strategy for manipulating antigen-specific T cells. We propose here that T-cell receptor (TCR) gene transfer is an effective approach for antigen-specific immunotherapy. We have confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig-transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis, arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. With this TCR, we demonstrated two applications of the TCR-transduced T cells. First, this arthritis-related TCR and the TNFRIg-transduced cells suppressed arthritis as a vector for therapeutic molecule. Second, arthritis-associated TCR and Foxp3-transduced cells suppressed arthritis progression and bone destruction as antigen-specific regulatory T cells. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy.