Combined Blockade of CD28/B7 and CD40/CD40L Costimulatory Pathways Prevents the Onset of Chronic Rejection

Субботин, Владимир; Sun, Hong; Chen, C; Aı̈touche, Abdelouahab; Valdivia, Luis A.; Fung, John J.; Starzl, Thomas E.; Rao, Abdul S.

doi:10.1016/s0041-1345(98)00100-6

Cited by 10 publications

(3 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In marked contrast to this study, MR-1-treated allografts developed intimal lesions, whereas the simultaneous blockade of both CD28 (CTLA-4 Ig) and CD40 (MR-1) signaling pathways was required to effectively inhibit chronic rejection (14). Using a murine aortic allotransplantation model, Subbotin et al also reported that the blockade of both CD28 and CD40L/CD40 costimulatory pathways was required to prevent chronic rejection (31). An explanation for the requirement of both CD28/CD40L blockade may be attributed to the full Agmismatched strain combinations used in the previous studies.…”

Section: Discussioncontrasting

confidence: 70%

CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants

Fischbein

Ardehali²,

Yun

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Chronic rejection remains the major obstacle to long term survival in heart transplant recipients. The cellular and molecular mechanisms that underlie chronic rejection are not known, and their discovery can form the basis of clinical intervention. Several investigators have suggested that the development of chronic rejection in solid organ transplants is dependent on help mediated by CD4+ lymphocytes. Importantly, the mechanism through which help is provided has not been fully delineated in transplant rejection. Using a murine heterotopic heart transplant model without immunosuppression, this study defines the functional role of CD4+ lymphocytes in chronic rejection. In an MHC class II-mismatched model, we demonstrate that chronic rejection was absolutely contingent on the presence of CD4+ lymphocytes. Importantly, here we report that signaling through CD40 can replace the requirement of CD4+ lymphocytes, demonstrated by the development of chronic rejection in CD4 knockout recipients treated with a CD40-activating mAb (FGK45). The return of rejection appears to be a CD8+ lymphocyte-dependent process, noted by the absence of rejection in FGK45-treated recombinase-activated gene knockout (CD4+ and CD8+ lymphocyte-deficient) recipients. The CD40 signaling pathway works independently of B7-CD28 costimulation, as indicated by the development of severe chronic rejection in CD28 knockout recipients. Importantly, this study provides evidence that CD40 ligand-targeted therapies may prevent chronic rejection only in strain combinations where CD4+ lymphocyte help is absolutely required.

show abstract

Section: Discussioncontrasting

confidence: 70%

CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants

Fischbein

Ardehali²,

Yun

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…However, blockade of CD40-CD40L and B7-CD28 is more efficacious at inhibiting rejection than blockade of either alone (40,41). Our results offer a plausible explanation for these findings since ICAM-1 is rapidly up-regulated by CD40L (39).…”

Section: Discussionmentioning

confidence: 64%

Intercellular Adhesion Molecule 1 Is Critical for Activation of CD28-Deficient T Cells

Gaglia

Greenfield

Mattoo

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Presentation of Ag to T lymphocytes in the absence of the requisite costimulatory signals leads to an Ag-specific unresponsiveness termed anergy, whereas Ag presentation in conjunction with costimulation leads to clonal expansion. B7/CD28 signaling has been shown to provide this critical costimulatory signal and blockade of this pathway may inhibit in vitro and in vivo immune responses. Although T cells from CD28-deficient mice are lacking in a variety of responses, they nonetheless are capable of various primary and secondary responses without the induction of anergy expected in the absence of costimulation. This suggests that there may be alternative costimulatory pathways that can replace CD28 signaling under certain circumstances. In this paper, we show that ICAM-1becomes a dominant costimulatory molecule for CD28-deficient T cells. ICAM-1 costimulates anti-CD3-mediated T cell proliferation and IL-2 secretion in CD28-deficient murine T cells. Furthermore, splenocytes from ICAM-1-deficient mice could not activate CD28-deficient T cells and splenocytes lacking both ICAM and CD28 fail to proliferate in response to anti-CD3-induced T cell signals. This confirms that not only can ICAM-1 act as a CD28-independent costimulator, but it is the dominant, requisite costimulatory molecule for the activation of T cells in the absence of B7/CD28 costimulation.

show abstract

“…Although blocking the CD40-CD154 pathway alone prevented acute rejection in organ transplantation models, it did not result in durable tolerance (54). This was, however, achieved by the coadministration of CTLA4Ig with or without rapamycin (55,56). The encouraging preclinical findings prompted introduction of anti-CD154 antibodies in a phase 1 clinical trial.…”

Section: Costimulation Blockade and Transplantation Tolerancethe Othe...mentioning

confidence: 99%

Abatacept and T-cell costimulation blockade—shifting the paradigm in the prevention of graft-versus-host disease

Chakrabarti,

Jaiswal

2023

Front. Hematol.

View full text Add to dashboard Cite

Despite advances in transplantation techniques and immunosuppressive therapies, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality, necessitating the use of innovative strategies for its prevention. T-cell activation plays a crucial role in the pathogenesis of GVHD, and T-cell costimulation blockade (COSBL) has emerged as a promising approach to prevent this devastating condition. This review aims to explore the concept of COSBL and its potential as a paradigm-shifting strategy in the prevention of GVHD, in the context of the existing modalities for the prevention of GVHD and the preclinical and clinical studies on COSBL. The unique property of abatacept (CTLA4Ig) is not just limited to dampening T-cell activation. The salutary effect of abatacept on natural killer (NK) cells and Tregs alike provides a unique opportunity to dissociate T-cell-mediated GVHD from NK cell-mediated graft-versus-leukemia. Further research is warranted to explore other modalities of COSBL, determine the optimal dosing and combinations for COSBL, and identify predictive biomarkers for patient stratification, ultimately paving the way for improved outcomes in hematopoietic cell transplantation recipients.

show abstract

Combined Blockade of CD28/B7 and CD40/CD40L Costimulatory Pathways Prevents the Onset of Chronic Rejection

Cited by 10 publications

References 3 publications

CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants

CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants

Intercellular Adhesion Molecule 1 Is Critical for Activation of CD28-Deficient T Cells

Abatacept and T-cell costimulation blockade—shifting the paradigm in the prevention of graft-versus-host disease

Contact Info

Product

Resources

About