Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

Kitazawa, Yoshiaki; Fujino, Masayuki; Sakai, Takahisa; Azuma, Haruhito; Kimura, Hiroyuki; Isaka, Yoshitaka; Takahara, Shiro; Hünig, Thomas; Ryo, Akihide; Li, Xiaokang

doi:10.1016/j.healun.2008.01.004

Cited by 24 publications

(20 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Perhaps counterintuitively, superagonistic anti-CD28 antibodies that potently stimulate T cell activation (55) have been observed to restore immune tolerance in several autoimmune and transplantation models (56)(57)(58). This presents something of a conundrum as to whether enhancing Treg (superagonists) or blocking effector cells (antagonists) is the better strategy.…”

Section: Anti-cd28 Specific Antibodiesmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

View full text Add to dashboard Cite

T cell activation is a key event in the adaptive immune system and vital in the generation of protective cellular and humoral immunity. Activation is required to generate CD4 effector T cell responses and provide help for B cell and cytotoxic T cell responses. While defective T responses to foreign antigen result in infectious pathology, over-reactive T cell responses against self-antigens result in autoimmunity and, in a transplantation setting, tissue rejection. Understanding how T cell activation is normally regulated is critical to therapeutic intervention and the CD28/CTLA-4 (CD152) pathway represents the initial activation checkpoint in molecular terms. In particular, while the CTLA-4 pathway is well established as an essential regulator of self-reactivity, its mechanism of action is still uncertain. Such mechanistic issues are important given its central position in T cell activation and the increasing number of therapeutic modalities aimed at manipulating the CD28/CTLA-4 pathway. Here, we provide an updated view of CTLA-4 biology, reviewing the established features of the system and highlighting its interplay with CD28. We then discuss how recent progress in our understanding of this pathway affects our interpretations following intervention. A Functional Overview of the CD28/CTLA-4 Pathway CD28 is expressed on the surface of the majority of na€ ıve CD4 and CD8 T cells and is the major costimulatory molecule in initial T cell activation. Together with engagement of the T cell receptor CD28 ligation results in the augmentation of many aspects of T cell-mediated immunity (1-3). Consequently, mice deficient in CD28 show an array of immune defects including impaired T cell activation, a lack of T cell help for B cells and poor memory T cell responses, all highlighting the importance of CD28 costimulation in the generation of effective T cell responses and immune memory.The immune stimulatory features of the CD28 pathway are triggered by engagement of two well-described ligands found on antigen-presenting cells (4). The two ligands CD80 (B7/BB1 or B7-1) and CD86 (B7-2) were, until recently, thought to be the sole ligands for CD28 and CTLA-4; however, there are recent reports that human (but not mouse) CD28 and CTLA-4, can also bind to the ICOS ligand (5). In addition, the PD-1 ligand, PD-L1 can also interact with CD80 (6). The significance of these novel interactions is still emerging and will not be discussed further here. Importantly, the expression of CD80 and CD86 is up-regulated in response to inflammatory stimuli including Toll-like receptor stimulation. As such, up-regulation of ligands is seen as a key link between innate ''danger'' signals and the triggering of an effective adaptive immune response (7). Despite structural and affinity differences (8) which would suggest functional differences, to date, the current view is that CD80 and CD86 have largely redundant or overlapping functions as represented in Figure 1 (9,10).In addition to binding to CD28, both CD80 and CD86 also bind to the inhibitory p...

show abstract

Section: Anti-cd28 Specific Antibodiesmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

View full text Add to dashboard Cite

show abstract

“…18,19 The latter property has been exploited in a plethora of rat and mouse models of autoimmunity, inflammation, and transplantation, with extremely encouraging results. [20][21][22][23][24][25][26][27][28][29][30][31] It was therefore a shock when TGN1412, a human CD28SA of the IgG4 subclass, caused a life-threatening cytokine release syndrome (CRS) during a first-in-man trial in March 2006. 32 This tragic outcome was unexpected not only because of the benign behavior of CD28SA in analogous rodent models, but also because TGN1412 itself was well tolerated in cynomolgous monkeys.…”

Section: Introductionmentioning

confidence: 99%

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

Römer

Berr

Avota

et al. 2011

Blood

Self Cite

129

150

View full text Add to dashboard Cite

Human volunteers receiving TGN1412, a humanized CD28-specific monoclonal antibody, experienced a life-threatening cytokine release syndrome during a recent trial. Preclinical tests using human PBMCs had failed to announce the rapid release of TNF, IFN-␥, and other toxic cytokines in response to this CD28 "superagonist" (CD28SA). CD28SA activate T-lymphocytes by ligating CD28 without overt engagement of the TCR. They do, however, depend on "tonic" TCR signals, which they amplify. Here we show that short-term preculture of PBMCs at high, but not at low, cell density results in massive cytokine release during subsequent stimulation with soluble TGN1412. Restoration of reactivity was cell-contact dependent, involved functional maturation of both monocytes and T cells, was sensitive to blockade by HLA-specific mAb, and was associated with TCR polarization and tyrosine phosphorylation. CD4 effector memory T cells were identified as the main source of proinflammatory cytokines. Importantly, responses to other T-cell activating agents, including microbial antigens, were also enhanced if PBMCs were first allowed to interact under tissue-like conditions. We provide a protocol, which strongly improves reactivity of circulating T cells to soluble stimulants, thereby allowing for more reliable preclinical testing of both activating and inhibitory immunomodulatory drugs. (Blood. 2011;118(26):6772-6782)

show abstract

“…A unique superagonistic anti-mouse CD28-specific monoclonal antibody (supCD28mAb) was developed to induce proliferation of all primary resting T cells without T-cell receptor (TCR) engagement, which potently stimulates and expands CD4+CD25+Treg cells over conventional CD4+CD25− T cells both in vitro and in vivo [11][12][13]. In keeping with the Th2-promoting effect of CD28 signals in co-stimulation, it was shown that T-cell activation with supCD28 primed CD4+T cells for Th2 differentiation in vitro, and induced IL-4 and IL-10 expression along with Th2-depengent immunoglobulin isotypes in vivo.…”

Section: Introductionmentioning

confidence: 99%

The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

Chen

Xie

Toyama

et al. 2011

International Immunopharmacology

Self Cite

View full text Add to dashboard Cite

Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

Cited by 24 publications

References 28 publications

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

Contact Info

Product

Resources

About