Abstract:
:Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
journal_name
Annu Rev Immunoljournal_title
Annual review of immunologyauthors
Feldmann M,Brennan FM,Maini RNdoi
10.1146/annurev.immunol.14.1.397subject
Has Abstractpub_date
1996-01-01 00:00:00pages
397-440eissn
0732-0582issn
1545-3278journal_volume
14pub_type
杂志文章,评审abstract::Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also interve...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.22.012703.104533
更新日期:2004-01-01 00:00:00
abstract::Inflammation is an unstable state. It either resolves or persists. Why inflammation persists and the factors that define tissue tropism remain obscure. Increasing evidence suggests that tissue-resident stromal cells not only provide positional memory but also actively regulate the differential accumulation of inflamma...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-032713-120252
更新日期:2015-01-01 00:00:00
abstract::The Notch pathway is gaining increasing recognition as a key regulator of developmental choices, differentiation, and function throughout the hematolymphoid system. Notch controls the generation of hematopoietic stem cells during embryonic development and may affect their subsequent homeostasis. Commitment to the T ce...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.23.021704.115747
更新日期:2005-01-01 00:00:00
abstract::Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and C...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.21.120601.141036
更新日期:2003-01-01 00:00:00
abstract::Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myelope...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.23.021704.115653
更新日期:2005-01-01 00:00:00
abstract::NK cells sit at the crossroads of innate and adaptive immunity and help coordinate tumor immunosurveillance and the immune response against pathogens. Balancing signals to NK cell precursors is crucial for their early development, when transcription factors compete to specify the different lymphocyte subsets. Despite ...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.24.021605.090700
更新日期:2006-01-01 00:00:00
abstract::Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that e...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-042718-041407
更新日期:2019-04-26 00:00:00
abstract::T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.21.120601.141110
更新日期:2003-01-01 00:00:00
abstract::While still incomplete, the first data concerning the biochemistry of T cell receptor-ligand interactions in cell-free systems seem to have considerable predictive value regarding whether a T cell response is strong or weak or suppressive. This data will help considerably in elucidating the mechanisms behind T cell re...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.16.1.523
更新日期:1998-01-01 00:00:00
abstract::Gene-chips contain thousands of nucleotide sequences that allow simultaneous analysis of the complex mixture of RNAs transcribed in cells. Like these gene-chips, major histocompatibility complex (MHC) class I molecules display a large array of peptides on the cell surface for probing by the CD8(+) T cell repertoire. T...
journal_title:Annual review of immunology
pub_type: 杂志文章
doi:10.1146/annurev.immunol.20.100301.064819
更新日期:2002-01-01 00:00:00
abstract::The diverse microbial populations constituting the intestinal microbiota promote immune development and differentiation, but because of their complex metabolic requirements and the consequent difficulty culturing them, they remained, until recently, largely uncharacterized and mysterious. In the last decade, deep nucl...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-032713-120238
更新日期:2015-01-01 00:00:00
abstract::T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along with T cell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multi...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-020711-075058
更新日期:2012-01-01 00:00:00
abstract::The gut-associated lymphoid tissue (GALT) faces a considerable challenge. It encounters antigens derived from an estimated 1014 commensal microbes and greater than 30 kg of food proteins yearly. It must distinguish these harmless antigens from potential pathogens and mount the appropriate host immune response. Local a...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-042718-041621
更新日期:2019-04-26 00:00:00
abstract::A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituita...
journal_title:Annual review of immunology
pub_type: 杂志文章
doi:10.1146/annurev.immunol.20.082401.104914
更新日期:2002-01-01 00:00:00
abstract::T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-032712-095956
更新日期:2013-01-01 00:00:00
abstract::The gastrointestinal tract harbors numerous commensal bacteria, referred to as the microbiota, that benefit host health by digesting dietary components and eliminating pathogens. The intestinal microbiota maintains epithelial barrier integrity and shapes the mucosal immune system, balancing host defense and oral toler...
journal_title:Annual review of immunology
pub_type: 杂志文章
doi:10.1146/annurev-immunol-070119-115104
更新日期:2020-04-26 00:00:00
abstract::The tripartite subdivision of lymphocytes into B cells, alphabeta T cells, and gammadelta cells has been conserved seemingly since the emergence of jawed vertebrates, more than 450 million years ago. Yet, while we understand much about B cells and alphabeta T cells, we lack a compelling explanation for the evolutionar...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.18.1.975
更新日期:2000-01-01 00:00:00
abstract::The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also reg...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.23.021704.115611
更新日期:2005-01-01 00:00:00
abstract::The transmembrane receptor Notch participates in diverse cell fate decisions throughout embryonic development. Notch receptors and their ligands are expressed in the mammalian thymus, raising the possibility that Notch could regulate T cell fate decisions. Expression of a constitutively activated form of Notch in deve...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.17.1.283
更新日期:1999-01-01 00:00:00
abstract::Major histocompatibility complex (MHC) class II molecules are heterodimeric cell surface proteins that are critically important for the development and function of cells in the immune system. In particular, the maturation of CD4+ T cells is dependent on the expression of MHC class II molecules on thymic epithelium, wh...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.iy.13.040195.002221
更新日期:1995-01-01 00:00:00
abstract::This review summarizes the general parameters of cell- and antibody-mediated immune protection and the basic mechanisms responsible for what we call immunological memory. From this basis, the various successes and difficulties of vaccines are evaluated with respect to the role of antigen in maintaining protective immu...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.21.120601.141045
更新日期:2003-01-01 00:00:00
abstract::T cell development involves stepwise progression through defined stages that give rise to multiple T cell subtypes, and this is accompanied by the establishment of stage-specific gene expression. Changes in chromatin accessibility and chromatin modifications accompany changes in gene expression during T cell developme...
journal_title:Annual review of immunology
pub_type: 杂志文章
doi:10.1146/annurev-immunol-092719-082622
更新日期:2020-04-26 00:00:00
abstract::MHC class I molecules are peptide receptors of stringent specificity which however still allow millions of different ligands. This is achieved by the following specificity characteristics summarized as allele specific peptide motifs: Peptides are of defined length, depending on the class I allele (either 8 or 9 residu...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.iy.11.040193.001241
更新日期:1993-01-01 00:00:00
abstract::The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.021908.132641
更新日期:2009-01-01 00:00:00
abstract::Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances ov...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-042718-041757
更新日期:2019-04-26 00:00:00
abstract::T and B cells share a common somatic gene rearrangement mechanism for assembling the genes that code for their antigen receptors; they also have developmental pathways with many parallels. Shared usage of basic helix-loop-helix E proteins as transcriptional drivers underlies these common features. However, the transcr...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-032712-100024
更新日期:2014-01-01 00:00:00
abstract::It is possible to create mice in which a planned alteration has been introduced at a specific locus in the genome. The planned alteration is first introduced into the genome of mouse embryonic stem (ES) cells in tissue culture. This is accomplished by homologous recombination between the targeted genomic locus and DNA...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.iy.10.040192.003421
更新日期:1992-01-01 00:00:00
abstract::The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more than 100 years ago and was originally defined as a liver-derived, blood-circulating sentinel system that classically mediates the opsonization and lyt...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev-immunol-042617-053245
更新日期:2018-04-26 00:00:00
abstract::The presence of intestinal intra-epithelial lymphocytes (IEL) has been appreciated for over 100 years. However, until recently, the IEL were thought to be simply another specialized component of the gut-associated lymphoid tissue (GALT), sharing the same origin as lymphocytes found in other GALT compartments such as t...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.iy.12.040194.002513
更新日期:1994-01-01 00:00:00
abstract::Recent structural information for complexes of cytokine receptor ectodomains bound to their ligands has significantly expanded our understanding of the macromolecular topology and ligand recognition mechanisms used by our three principal shared cytokine signaling receptors-gp130, gamma(c), and beta(c). The gp130 famil...
journal_title:Annual review of immunology
pub_type: 杂志文章,评审
doi:10.1146/annurev.immunol.24.021605.090616
更新日期:2009-01-01 00:00:00