Persistent Long-Term Changes In Lymphocyte Subsets Induced By Polyclonal Antibodies1

Abstract. Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 Ϯ 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 Ϯ 290/mm 3 , 553 Ϯ 596/mm 3 , and 66 Ϯ 62/mm 3 , respectively. CD4 levels were positively related to transplant duration (r ϭ 0.32; P ϭ 0.02) and inversely related to age (r ϭ 0.35; P ϭ 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 Ϯ 170/mm 3 versus 531 Ϯ 290/mm 3 ; P Ͻ 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P Ͻ 0.0001). A CD4 cell count in the highest quartile (Ͼ663/mm 3 ) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.Stable renal transplant recipients (RTR) have disproportionately high rates of arteriosclerotic outcomes (1). An increased prevalence of traditional cardiovascular risk factors cannot fully explain this increased incidence of CVE in the transplant population (2), and our group has recently emphasized the role of nontraditional cardiovascular risk factors, such as hyperhomocysteinemia (3). A recent study from the USRDS registry showed an increased cardiovascular mortality in RTR having received polyclonal antilymphocyte globulins (4), suggesting either that intense immunosuppression may accelerate native atherosclerosis or that polyclonal antithymocyte globulins exerts specific longterm detrimental effects on the course of atherosclerosis. Nevertheless, interpretation of this finding is challenged by the fact that the atherosclerotic lesion contains large number of immune cells, particularly macrophages and T cells. Furthermore, atherosclerosis is associated with systemic immune responses, including inflammation.On the other hand, several animal studies have shown that immunosuppression may accelerate native atherosclerosis (5-8).Moreover, an increased incidence of cardiovascular events has been reported in AIDS patients (9), and recent reports suggest a correlation between intensity of immunodeficiency and presence of atherosclerotic plaques (10). Lastly, a significant decrease in CD4 cells has been described in the blood of atomic bomb survivors, and an increased inci...

Section: Discussionmentioning

confidence: 99%

CD4 Cell Lymphopenia and Atherosclerosis in Renal Transplant Recipients

Ducloux

Challier²,

Saas³

et al. 2003

“…[3][4][5] The clinical consequences of ATG-induced CD8 T-cell activation are poorly known. However, recent data emphasize the effect of T-lymphocyte activation in atherosclerosis.…”

Section: Cd4mentioning

confidence: 99%

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

Ducloux¹,

Courivaud

Bamoulid

et al. 2014

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.

“…1,2 These antibodies produce profound T cell depletion via complement-dependent lysis and Fas/Fas ligand-mediated apoptosis. 3,4 Although T cell regeneration generally occurs in the months after ATG administration, Muller et al 5 reported that ATG may induce persistent changes in T cell subsets characterized by a low CD4 T cell count and a CD8 T cell expansion.…”

mentioning

confidence: 99%

Prolonged CD4 T Cell Lymphopenia Increases Morbidity and Mortality after Renal Transplantation

Ducloux

Courivaud

Bamoulid

et al. 2010

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts Ͻ300/mm 3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for Ͼ1 year (24.1 versus 7.6%; P Ͻ 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P ϭ 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3 ϩ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P ϭ 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P ϭ 0.013). In summary, prolonged polyclonal anti-thymocyte globulin-induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections. Broad T cell depletion by polyclonal anti-thymocyte globulins (ATG) has been used for many years as a part of immunosuppressive treatment in transplantation. These polyclonal antibodies are a complex mixture of antibodies with multiple specificities directed to both T and non-T cells. 1,2 These antibodies produce profound T cell depletion via complement-dependent lysis and Fas/Fas ligand-mediated apoptosis. 3,4 Although T cell regeneration generally occurs in the months after ATG administration, Muller et al. 5 reported that ATG may induce persistent changes in T cell subsets characterized by a low CD4 T cell count and a CD8 T cell expansion.