Mechanisms of targeting cd28 by a signaling monoclonal antibody in acute and chronic allograft rejection1

Dong, Victor; Yuan, Xin; Coito, Ana J.; Waaga, Ana Maria; Sayegh, Mohamed H.; Chandraker, Anil

doi:10.1097/00007890-200204270-00021

Cited by 33 publications

(26 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we have previously described (39), administration of DST on the day of transplant followed by a single injection of hCTLA4Ig on day 2 resulted in all of the allografts achieving long-term survival (MST Ͼ 200, n ϭ 6, p Ͻ 0.001 compared with untreated controls and hCTLA4Ig alone). However, DST showed no significant additional effect on graft survival when combined with anti-CD134L Ab (MST: 15.5 Ϯ 1.732 days; n ϭ 4, p ϭ NS) (Fig.…”

Section: The Effect Of Cd134-cd134l and Cd28-b7 Blockade On Cardiac Asupporting

confidence: 54%

“…Heterotropic vascularized cardiac transplants were performed by standard microvascular techniques (39,40). Donor hearts were engrafted into the recipient's abdomen using an end-to-side anastomosis of the donor ascending aorta and pulmonary artery with the recipient's abdominal aorta and vena cava.…”

Section: Cardiac Transplantationmentioning

confidence: 99%

“…Donor skin was engrafted onto the recipient's lumbar region and checked daily for signs of rejection (39,40).…”

Section: Skin Transplantationmentioning

confidence: 99%

See 2 more Smart Citations

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Yuan

Salama

Dong

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-γ-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 ± 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 ± 2.8 days) as did CTLA4Ig (MST: 21.5 ± 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 ± 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.

show abstract

Section: The Effect Of Cd134-cd134l and Cd28-b7 Blockade On Cardiac Asupporting

confidence: 54%

Section: Cardiac Transplantationmentioning

confidence: 99%

See 1 more Smart Citation

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Yuan

Salama

Dong

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…[5][6][7] However, these approaches have been limited to blocking positive T-cell costimulation through treatment of the recipient, rather than modifying the context of antigen presentation by donor tissue. Here, we studied the role of negative costimulatory molecule expression within donor allograft versus recipient in the regulation of the alloimmune response in vivo.…”

Section: Clinical Perspective P 669mentioning

confidence: 99%

“…The ELISpot assay (R&D Systems, Minneapolis, Minn) was adapted to measure the frequency of alloreactive T cells producing interferon (IFN)-␥-and interleukin (IL)-4 -secreting cells, as described previously. 17,18,24 The frequencies of cytokine-secreting cells were expressed as the number of cytokine-producing spots per 0.5ϫ10 6 splenocytes.…”

Section: Elispot Assaymentioning

confidence: 99%

Critical Role of Donor Tissue Expression of Programmed Death Ligand-1 in Regulating Cardiac Allograft Rejection and Vasculopathy

et al. 2008

Self Cite

View full text Add to dashboard Cite

Background-Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo. Methods and Results-We used established major histocompatibility complex class II-and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1-and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1 Ϫ/Ϫ donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1Ϫ/Ϫ recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1 Ϫ/Ϫ donor grafts in transplanted wild-type recipients. Conclusions-This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy. (Circulation. 2008;117: 660-669.)

show abstract

CD28 expression by peripheral blood lymphocytes as a potential predictor of the development of de novo malignancies in long-term survivors after liver transplantation

et al. 2011

View full text Add to dashboard Cite

At present, no method is available for accurately monitoring the degree of immunosuppression induced by antirejection therapies. The aim of this study was to determine whether CD28 and CD38 expression by peripheral blood mononuclear cells could be useful in predicting the development of de novo malignancies after liver transplantation. Flow cytometry analysis was used to measure the expression of CD28 and CD38 by peripheral blood lymphocytes in 134 stable, long-term survivors of liver transplantation. Patients who developed a de novo malignancy after undergoing a medical checkup were entered into a cancer group. Twenty-two patients (16.4%) developed at least 1 de novo malignancy over a mean interval of 22 6 14 months (1.2-49.4 months) after the checkup. The mean frequency of CD28 þ CD8 þ cells was significantly lower in the cancer group versus the noncancer group (39% 6 22 versus 51% 6 21, P ¼ 0.008), but CD38 expression was similar in the 2 groups. Multivariate analysis indicated that an age greater than 50 years (odds ratio ¼ 5.81) and a low frequency of CD28 þ CD8 þ cells at the time of the checkup (odds ratio ¼3.16) were the only significant predictors of the development of de novo malignancies (P ¼ 0.027). The actuarial proportion of patients with de novo malignancies was significantly lower when the frequency of CD28 þ CD8 þ cells was greater than or equal to 40% instead of less than 40% (P ¼ 0.01). Flow cytometry measurements of CD28 expression by peripheral blood lymphocytes may facilitate the identification of patients at a high risk of developing de novo malignancies. Further prospective studies are necessary to determine whether such measurements could have a place in routine clinical practice to enable the intensity of immunosuppression to be minimized in patients who have an increased risk of developing cancer.

show abstract

Mechanisms of targeting cd28 by a signaling monoclonal antibody in acute and chronic allograft rejection1

Cited by 33 publications

References 32 publications

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Critical Role of Donor Tissue Expression of Programmed Death Ligand-1 in Regulating Cardiac Allograft Rejection and Vasculopathy

CD28 expression by peripheral blood lymphocytes as a potential predictor of the development of de novo malignancies in long-term survivors after liver transplantation

Contact Info

Product

Resources

About