Polyclonal Rabbit Antithymocyte Globulin Triggers B-Cell and Plasma Cell Apoptosis by Multiple Pathways

Zand, Martin S.; Vo, Thuong; Huggins, Jennifer; Felgar, Raymond E.; Liesveld, Jane L.; Pellegrin, Tina; Bozorgzadeh, Adel; Sanz, Igñacio; Briggs, Benjamin

doi:10.1097/01.tp.0000164159.20075.16

Cited by 220 publications

(181 citation statements)

References 43 publications

Supporting

Mentioning

172

Contrasting

Unclassified

Order By: Relevance

“…ATG also induces B-cell depletion. 24 Interestingly, even when the effect of B cells on atherosclerosis is subset dependent, B-cell depletion has been associated with atherosclerosis progression. 25 Compelling data from both animal models and other human populations suggest CD8 + activation as the trigger of ATG-induced atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

Ducloux¹,

Courivaud

Bamoulid

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)-induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87631 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8 + T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs.

show abstract

Section: Discussionmentioning

confidence: 99%

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

Ducloux¹,

Courivaud

Bamoulid

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Interestingly, because certain epitopes are shared between T and B cells and because pediatric thymi also contain CD20 + B cells and CD138 + plasma cells, ATG contain IgGs directed against these latter subsets. 39 As a result, in vitro studies have shown that ATG induces apoptosis of naive, activated B cells and bone marrow resident plasma cells at clinically relevant concentrations (1-100 ng/ml). 39 However, the importance of ATGinduced plasma and/or B cell depletion in vivo has not been clearly shown.…”

Section: Effect Of Induction Therapy On Dndsa Generationmentioning

confidence: 99%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

View full text Add to dashboard Cite

The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

show abstract

“…Later in the study, cohort 2 also received a 4-day course of anti-thymocyte globulin (ATG), which is the purified immunoglobulin (Ig)G fraction of rabbits or horses that are immunized with human thymocytes or T cell lines. ATG depletes peripheral lymphocytes through complement-dependent lysis or activation-associated apoptosis [13][14][15]. ATG formulations have been used in human transplantation for decades [16].…”

Section: Introductionmentioning

confidence: 99%

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Meyer

Walker

Dewane

et al. 2015

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryIn this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.

show abstract

Polyclonal Rabbit Antithymocyte Globulin Triggers B-Cell and Plasma Cell Apoptosis by Multiple Pathways

Abstract: Polyclonal rATG induces complement-independent apoptosis of naive, activated, and plasma B cells. This effect appears to involve the caspase- and cathepsin-mediated apoptosis pathways.

Cited by 220 publications

References 43 publications

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Contact Info

Product

Resources

About