Significance of Intragraft CD138+Lymphocytes and p-S6RP in Pediatric Kidney Transplant Biopsies

Mattel Children's Hospital UCLA, Division of Pediatric Nephrology, Los Angeles, CA, USA.
Transplantation (Impact Factor: 3.83). 10/2010; 90(8):875-81. DOI: 10.1097/TP.0b013e3181f24e3c
Source: PubMed

ABSTRACT We have previously shown that intragraft CD20+ B cells are associated with acute cellular rejection (ACR) and allograft loss. Phosphorylation of S6 ribosomal protein, a downstream target of the PI3K/Akt/mTOR pathway, promotes growth and proliferation of cells and could identify metabolically active cells such as alloantibody secreting plasma cells. Because CD20+ lymphocytes can differentiate into CD138+ plasma cells, we aimed to identify functionally active plasma cells by using intragraft CD138 quantification and p-S6RP staining and correlate these results with allograft rejection, function, and survival.
We examined 46 renal transplant biopsies from 32 pediatric patients who were biopsied for clinical suspicion of rejection. Immunohistochemical staining for C4d, CD20, CD138, and p-S6RP was performed. Patient creatinine clearance and graft status was followed up postbiopsy.
Patients with greater than or equal to six CD138+ cells/high power field (hpf) had worse graft survival with a hazard ratio of 3.4 (95% CI 1.3-9.2) 2 years postbiopsy compared with those with 0 to 5 cells/hpf (P=0.016). CD138+ cells were stained for p-S6RP, indicating functionally active plasma cells. They were associated with ACR (P=0.004) and deteriorating graft function (R=0.22, P=0.001). Intragraft CD20+ and CD138+ cells found together in ACR were associated with poorer graft survival than either marker alone, hazard ratio 1.5 (95% CI 1.1-2.2, P=0.01).
A threshold of greater than or equal to six CD138+ metabolically active plasma cells per hpf, coexisting with CD20+ B cells, was associated with poor allograft function and survival. This may represent an additional antibody-mediated process present in the setting of ACR and could play an important role in characterization and treatment of transplant rejection.

Download full-text


Available from: Robert Ettenger, Sep 29, 2015
33 Reads
  • Source
    • "Chronic AMR has been associated with the de novo development of post-transplant donor-specific antibodies (DSA) (21). These antibodies are produced by B-cells that have developed high-affinity receptors targeting HLA mismatches arising from the graft and have undergone class switching from IgM to IgG with subsequent maturation to plasma cells and memory B-cells (22,23). Memory B-cells and memory T-cells are difficult to address using current immunosuppressive therapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Solid organ transplantation has transformed the lives of many children and adults by providing treatment for patients with organ failure who would have otherwise succumbed to their disease. The first successful transplant in 1954 was a kidney transplant between identical twins, which circumvented the problem of rejection from MHC incompatibility. Further progress in solid organ transplantation was enabled by the discovery of immunosuppressive agents such as corticosteroids and azathioprine in the 1950s and ciclosporin in 1970. Today, solid organ transplantation is a conventional treatment with improved patient and allograft survival rates. However, the challenge that lies ahead is to extend allograft survival time while simultaneously reducing the side effects of immunosuppression. This is particularly important for children who have irreversible organ failure and may require multiple transplants. Pediatric transplant teams also need to improve patient quality of life at a time of physical, emotional and psychosocial development. This review will elaborate on the long-term outcomes of children after kidney, liver, heart, lung and intestinal transplantation. As mortality rates after transplantation have declined, there has emerged an increased focus on reducing longer-term morbidity with improved outcomes in optimizing cardiovascular risk, renal impairment, growth and quality of life. Data were obtained from a review of the literature and particularly from national registries and databases such as the North American Pediatric Renal Trials and Collaborative Studies for the kidney, SPLIT for liver, International Society for Heart and Lung Transplantation and UNOS for intestinal transplantation.
    Clinics 12/2013; 69(Suppl 1):28-38. DOI:10.6061/clinics/2014(Sup01)06 · 1.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the decrease in incidence of early clinical and subclinical rejection and increased 1-year graft survival in renal transplant patients, the rate of graft loss after the first year has been only moderately improved. Protocol biopsies obtained in the first year have shown rapid increase in the prevalence of IF/TA. This finding has been correlated with later allograft dysfunction and loss, mostly in cases of concomitant interstitial inflammation and fibrosis (1). The landmark study by Nankivell et al., performed in recipients of organs from deceased young donors under early cysclosporin-based immunosuppression, suggested two distinct phases of injury involved in IF/TA: an early tubulo-interstitial damage from ischemic injury and allograft rejection and, beyond 1 year, microvascular, glomerular and additional tubulo interstitial injury interpreted as secondary CsA toxicity (2). Since this publication, chronic antibody-mediated rejection has been better identified as leading causes of late graft dysfunction. Moreover, a recent study showed that most cases of kidney graft loss have an identifiable cause that is not idiopathic IF/TA or CNI toxicity and that alloimmunity remains the most common mechanism leading to failure (3). Thus, with the current immunosuppressive regimens and the input of molecular phenotyping, one may question the natural history of IF/TA.
    American Journal of Transplantation 04/2011; 11(4):647-9. DOI:10.1111/j.1600-6143.2011.03456.x · 5.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AimsThe cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown.Methods and resultsExpression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β, and with infiltrating CD3(+)T-cells and CD68(+)monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-β transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts.Conclusion Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.
    European Heart Journal 11/2012; 34(25). DOI:10.1093/eurheartj/ehs375 · 15.20 Impact Factor
Show more