Transplant Immunology 23 (2010) 209–214
Contents lists available at ScienceDirect
Transplant Immunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t r i m
Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols Kelly Hire, Bernhard Hering, Pratima Bansal-Pakala ⁎ Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
a r t i c l e
i n f o
Article history: Received 7 May 2010 Received in revised form 21 May 2010 Accepted 11 June 2010 Keywords: sCD30 Islet allograft Transplantation tolerance
a b s t r a c t Despite advances in islet transplantation, challenges remain in monitoring for anti-islet immune responses. Soluble CD30 (sCD30) has been investigated as a predictor of acute rejection in kidney, lung, and heart transplantation as well as in a single study in human islet cell recipients. In this study, sCD30 levels were retrospectively assessed in 19 allograft recipients treated with three different immunosuppression induction therapies. Soluble CD30 levels were assessed at pre-transplant; early post-transplant (day 4–day 7); onemonth post-transplant; and late post-transplant (day 90–day 120) and then correlated with eventual graft outcomes at 1-year follow-up. Results showed no correlation between mean serum sCD30 levels at any point in time pre- or post-transplant and graft function at 1-year follow-up. However, analysis demonstrated that mean sCD30 levels at day 28 or day 90–day 120 decreased from pre-transplant levels in recipients with long-term islet allograft function compared to recipients with partial or non-graft function (a decrease of 43.6 ± 25.6% compared to 16.7 ± 35.2%, p b 0.05). In another ﬁnding, immunosuppression with the ATG protocol led to a greater reduction in sCD30 levels post-transplant overall. A larger reduction post-transplant correlated with full graft function. The results demonstrate that a relative reduction in sCD30 levels post-transplant may be applicable as a biomarker to monitor graft function in islet allograft recipients. Additionally, knowledge of the impact of various immunosuppression protocols on the timing and extent of changes in post-transplant sCD30 levels could aid in patient-speciﬁc tailoring of immunosuppression. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Although islet transplantation for the purposes of achieving normoglycemia is in the comparatively early stages of development, many of the challenges in advancing the therapy are similar to those encountered in solid organ transplantation. Immune-mediated rejection must be controlled with immunosuppressive drugs entailing its own problems including an increased risk for graft damage, infections, and malignancies. These risks could be reduced by minimizing immunosuppression through patient-speciﬁc regimens rather than empiric dosing. Immunological monitoring is therefore critical to maintain full graft function and also to enable tailoring of immunosuppression induction protocols. As is the case with kidney, liver, and heart transplantation, a rapid and validated method of monitoring islet allograft function and rejection is necessary for effective patient
Abbreviations: sCD30, soluble CD30; ATG, anti-thymocyte globulin. ⁎ Corresponding author. Schulze Diabetes Institute, Department of Surgery, University of Minnesota, 424 Harvard Street SE, Minneapolis MN 55455, USA. Tel.: + 1 612 624 1430; fax: + 1 612 626 5855. E-mail address: [email protected]
(P. Bansal-Pakala). 0966-3274/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.trim.2010.06.007
management. There is a need for an accurate, speciﬁc, and minimally invasive method to identify rejection to enable early intervention with additional therapies at a point in time most likely to result in successful rescue of an allograft at-risk of losing function. However, real-time monitoring of islet allografts is hindered by an inability to continually monitor for rejection events directly at the site of transplant. Instead, rejection events are monitored by way of indicative markers in peripheral circulation including blood glucose and c-peptide values. However, rising blood glucose and declining c-peptide levels indicate a graft that has already failed beyond the point of rescue. These markers, therefore, are not useful in a therapeutic plan for returning function. Biopsies for histological analysis can be performed to examine T-cell migration prior to inﬁltration of the islet graft, but due to the invasive nature of this procedure, it is not a viable method of monitoring graft function over an extended period of time. Ideally, islet allograft recipients could be tested and monitored serially pre- and post-transplant for markers found in peripheral circulation that are either predictive indicators of graft success or early signs of rejection post-transplant. Such a strategy would enable timely intervention and treatment of failing grafts. The search for a test suitable for the on-going monitoring of grafts and the early recognition of acute rejection post-transplant has proven
K. Hire et al. / Transplant Immunology 23 (2010) 209–214
challenging with many strategies failing to prove efﬁcacy. Recently a number of immunological factors have been investigated for their predictive value. Of these, CD30 has been studied in the context of kidney, liver, and heart transplantation and in a more limited context in islet transplantation [1–6]. CD30 is a 120-kDa glycoprotein member of the tumor necrosis factor (TNF) receptor family and is expressed on the surface of activated T cells. CD30 signaling has been shown to play a role in the development of Th2 cells and the release of Th2 cytokines . As the T cells are activated, a smaller, soluble fragment (sCD30) is cleaved from the membrane bound form and is released into the serum. sCD30 is detectable in the periphery through serum assays such as ELISAs. Low levels of sCD30 are present at all times, even in healthy individuals. However, elevated levels of sCD30 have been noted during pregnancy, viral infection, autoimmune disorders such as rheumatoid arthritis and lupus erthematosus, lymphoma, or episodes of allosensitization [2–6]. Previous studies investigating the application of sCD30 levels to predict graft function in solid organ transplants have reported differing results. In some studies, elevated pre-transplant levels of sCD30 correlated with a higher risk of kidney [7–16], lung , and liver allograft rejection or non-function . However, other studies have found no correlation between pre-transplant sCD30 levels and graft function in kidney [18–26], liver , and heart allografts [28,29], suggesting that pre-transplant sCD30 levels are not necessarily predictive of eventual graft function. It has also been argued that sCD30 is a critical marker of rejection and should be used in posttransplant monitoring to evaluate on-going graft function [12,13,20]. While numerous studies have examined sCD30 levels in the context of solid organ transplantation, investigation of sCD30 levels in islet allograft transplantation is in the early stages. Because the number of islet allograft transplants performed is small compared to the number of solid organ transplants, investigation of the mechanisms of islet allograft tolerance must be conducted with smaller recipient numbers. The only previous study to examine sCD30 levels in islet allograft recipients found that sCD30 levels increased prior to rejection events and then decreased to levels thought to be “low risk” after the rejection event had passed . Therefore, it has been suggested evaluation of pre-transplant sCD30 levels could enable identiﬁcation of islet allograft recipients at higher risk of rejection. The present study is the second to investigate the correlation of sCD30 levels in recipients receiving islet allograft transplants with eventual graft outcome. 2. Objective The aim of this pilot study was to retrospectively evaluate the correlation between sCD30 levels and eventual graft outcome in 19 islet allograft recipients who participated in three clinical trials using different immunosuppressive induction therapies. 3. Materials and methods
clinical trials conducted between July 2001 and March 2005 were analyzed. Fourteen received single-donor islet allografts; 4 received 2 separate islet allografts, and 1 received 3 separate islet allografts during the course of treatment. Prior to islet allografts, recipients received induction therapies speciﬁc to the particular study: 6 recipients received ATG; 5 recipients received hOKT3γ-ala,ala; and 8 recipients received rabbit ATG and daclizumab (Table 1). One-year results of the transplant studies including details of the patient demographics and immunosuppressive regimens have been previously published for recipients receiving ATG  and ATG and daclizumab . The ﬁndings of the hOKT3γ-ala,ala study were made available (B.H., unpublished data, March 2010). The patient demographics of this study were similar to those in a previously published clinical study involving hOKT3γ-ala,ala . This study was approved by the Institutional Review Board at the University of Minnesota Medical Center. Written informed consent was obtained from all participants. 3.2. Patient follow-up and classiﬁcation of transplant function Soluble CD30 levels of participating recipients were analyzed at the following time points; pre-transplant; early post-transplant (day 4–day 7); day 28; and late post-transplant (day 90–day 120) and then correlated with eventual islet transplant outcomes at 1-year follow-up. Recipients were classiﬁed based on the ability to achieve insulin independence in the ﬁrst year after transplant. Recipients were classiﬁed as having full graft function if fasting blood glucose levels below 126 mg/dl (7.0 mmol/l) and 2-hour postprandial levels below 180 mg/dl (10.0 mmol/l) were maintained after discontinuation of insulin. Recipients with a dependence on exogenous insulin were classiﬁed as having partial graft function (basal or arginine-stimulated C-peptide levels of 0.5 ≥ ng/ml and HbA1c b 7%) or no graft function (absence of basal and arginine-stimulated C-peptide levels). 3.3. Soluble CD30 assay Serum samples were stored at − 70 °C prior to testing, and serum sCD30 levels were determined by using the commercially available human sCD30 ELISA kit (Bender MedSystems, Vienna, Austria) per the manufacturer's instructions. Brieﬂy, duplicate wells of a 1:4 dilution of sera were added to a 96-well plate pre-coated with anti-human CD30 mAb. An HRP-conjugated with the secondary antibody was added to all wells, and the plate was incubated at room temperature while gently rotating for 3 h. After washing, a TMB substrate solution was added to all wells and the color reaction monitored for up to 1 h. Stop solution was then added and plates were read using a SpectraMax M5 microplate reader and analyzed using SoftMax Pro (Molecular Devices, Sunnyvale, CA). The sCD30 ELISA kit used in this study has a detection limit of 0.3 ng/ml, according to the product labeling.
3.4. Statistical analysis
Serum samples from 19 type 1 diabetic recipients who received a total of 25 islet allografts in the course of three different single-center
Data have been presented as either mean values of sCD30 present in the serum (ng/ml) or as a percentage reduction of sCD30 present
Table 1 Recipient information by immunosuppression protocol and graft function. Study
Total no recipients per study
No recipients with full graft function (N 1 year)
No recipients with partial/ non-function (1 year)
Bellin et al.  Hering et al.  BH, unpublished data, March 2010
ATG, etanercept, cycloporine, everolimus ATG, daclizumab, etanercept, sirolimus, tacrolimus hOTK3γ-ala,ala, sirolimus
6 8 5
2 5 2
4 3 3
K. Hire et al. / Transplant Immunology 23 (2010) 209–214
Fig. 1. Graft outcome is not a function of pre- and post-transplant sCD30 levels. Plus sign — all transplants (n = 25); closed triangles — transplants with full graft function at 1 year post-transplant (n = 13); open triangles — transplants with partial or no graft function at 1 year post-transplant (n = 12). No correlation is shown between eventual graft outcome and soluble CD30 levels pre-transplant. (a) day 4–day 7 (b) day 28 (c), or day 90–day 120 (d). NS = not signiﬁcant.
relative to pre-transplant levels. Comparisons were analyzed using the two-tailed t test. P values b0.05 were considered signiﬁcant.
levels with a mean increase of 24.3 ± 46.8%. The increase was transient, returning to near baseline levels by day 28, and then showing a moderate reduction by day 90–day 120 (Fig. 3).
4. Results 4.1. Correlation between mean sCD30 levels at various time points and graft outcome Because possible sensitization of recipients due to rejection of the ﬁrst transplant may have a dramatic effect on the sCD30 levels prior to subsequent transplants, sCD30 levels prior to subsequent transplants were included as pre-transplant samples for the purposes of this analysis . Pre-transplant sCD30 levels in the recipients of 25 islet allograft transplants ranged from 10 to 80 ng/ml. There was no correlation between mean pre-transplant sCD30 levels and graft function at 1-year follow-up. As shown in Fig. 1a, the mean pre-transplant CD30 level in recipients who had full graft function following islet allograft was 31.9 ± 17.3 ng/ml compared to 28.5 ± 17.2 ng/ml in those with partial or non-functioning grafts. Similarly, there were no signiﬁcant differences in mean sCD30 levels in recipients with full graft function (13 of 25 transplants) and those with partial/non-functioning grafts at other time points (12 of 25 transplants) (Fig. 1b–d). The mean sCD30 level early post-transplant (day 4–day 7) was 20.7 ± 12.2 ng/ml in recipients with full graft function compared to 23.1 ± 11.3 ng/ml in those with partial or non-functioning grafts. Comparative levels were 15.9 ± 9.1 ng/ml and 21.2 ± 15.8 ng/ml at day 28 and 19.6 ± 18.4 ng/ml and 23.5 ± 9.7 ng/ml later post-transplant. 4.2. Correlation between relative reduction in sCD30 levels at various time points and graft function
4.4. Correlation between timing of changes in sCD30 levels and graft function and immunosuppressive induction therapy used The ATG-based induction protocol led to overall reduction in sCD30 levels, and a larger reduction post-transplant was correlative with full graft function. A greater reduction was observed at day 4–day 7 and day 28 in recipients with functioning grafts compared to partial or non-functioning grafts. Recipients who received immunosuppressive induction with ATG and who had full graft function at one year exhibited a greater mean reduction in sCD30 level early post-transplant than those without full graft function. The reduction for recipients with full function primary transplants was 74.6 ± 17.6% compared to 40.5 ± 13.4% those without full function (Fig. 4a). Recipients receiving a combination of ATG and daclizumab who had full graft function demonstrated a signiﬁcantly greater mean difference in sCD30 reductions later in treatment compared to those with partial or non-functioning grafts with a 64.7 ± 11.9% reduction compared to a 0.08 ± 14.1% increase for recipients with partial or nonfunctioning grafts, p b 0.005 (Fig. 4c). The hOKT3γ-ala,ala protocol resulted in an early increase in sCD30 levels that also correlated to partial or non-functional grafts. Soluble CD30 levels increased early posttransplant (day 4–day 7) when compared to pre-transplant levels (Fig. 4a). However, in the subset of these recipients who exhibited full function one year post-transplant, early post-transplant sCD30 levels decreased slightly compared to pre-transplant levels.
While there was no correlation between sCD30 levels and graft outcome at any timepoint pre- or post-transplant (as seen in Fig. 1), changes in post-transplant levels were then compared to pre-transplant levels for each recipient to establish a percent reduction of sCD30, as a method of compensating for the high individual pre-transplant variability seen within the transplant recipients. A relative reduction in the sCD30 level at day 28 or day 90–day 120 post-transplant compared to the pre-transplant level was observed in 19 of the 25 transplants. Mean sCD30 levels at the day 28 or day 90–day 120 decreased up to 50% compared to pre-transplant levels following transplants resulting in long-term islet allograft function, whereas the mean sCD30 level decreased to a lesser extent following transplants resulting in partial graft function (Fig. 2). Reduction in the sCD30 level was evident early post-transplant (day 4–day 7) compared to pre-transplant, but did not signiﬁcantly correlate with graft function (mean of 25.9 ± 35.6% for full graft function compared to 6.9 ± 40.1% with partial or non-graft function). However, by day 28, there was a signiﬁcantly greater reduction in sCD30 levels in transplants with full graft function compared to those with partial or non-function within one year of transplant. Soluble CD30 decreased 43.6 ± 25.6% in transplants with full graft function, compared to 16.7 ± 35.2% in those with partial or non-function, p b 0.05 (Fig. 2). 4.3. Correlation between sCD30 levels and immunosuppressive induction therapy The impact of three distinct induction immunosuppression therapies on sCD30 levels was assessed by comparing sCD30 levels pre- and post-primary transplant. When sCD30 levels were assessed according to the immunosuppressive induction therapy recipients received, it was found that induction with ATG or a combination of ATG and daclizumab led to a signiﬁcantly greater reduction in sCD30 levels early post-transplant compared to recipients receiving hOKT3γ1-ala,ala, p b 0.01 and p b 0.05 respectively (Fig. 3). The reduction in mean sCD30 level with ATG was 53.9 ± 22.8% compared to 30.1 ± 18.9% with a combination of ATG and daclizumab. The reduction in sCD30 achieved with ATG or a combination of ATG and daclizumab persisted through day 120. Conversely, induction with hOKT3γ1-ala,ala led to an early increase in sCD30
Fig. 2. Transplants with full graft function (solid columns, n = 13)) exhibited a larger reduction in sCD30 from pre-transplant levels than transplants with partial or no graft function (open columns, n = 12). The reduction in sCD30 was calculated as a percent change from pre-transplant levels. * = p b 0.05.
K. Hire et al. / Transplant Immunology 23 (2010) 209–214
Fig. 3. Recipients receiving ATG or ATG and daclizumab for their induction immunosuppression with the primary transplant show a marked reduction in sCD30 levels compared to pre-transplant levels. Conversely, hOKT3γ-ala,ala shows an increase in sCD30 levels early post-transplant (a), but a reduction later at day 28 (b) and day 90– day 120 (c). * = p b 0.05, ** = p b 0.01. See Table 1 for information recipient numbers within groups.
5. Discussion Soluble CD30 has been extensively studied as a prognostic tool for allograft rejection, yet no consensus has been reached [2– 5,17,22,25,26,28,29]. Most studies have focused on the correlation between pre-transplant sCD30 levels and eventual graft outcome. However, high variability in pre-transplant sera calls into question the use of sCD30 as a feasible marker for use in predicting allograft outcome . In contrast to Saini et al. who conducted the ﬁrst study of sCD30 levels in islet transplantation , we found no correlation between pre-transplant serum sCD30 levels and graft outcome. It is suspected that the high variability in the pre-transplant sCD30 levels of recipients in this study led to the ﬁnding of non-signiﬁcance. While several previous studies involving kidney, lung, and islet transplants have also indicated that there is a threshold sCD30 level that must be prior to onset of graft rejection, the actual values of these thresholds are arbitrary. Additionally, there is great variation in the thresholds between studies with the lowest cut-off point of a positive sCD30 level of 20 U/ml [17,34] to an upper-cut-off point of 124 U/ml . Numerous recipients exhibited sCD30 levels above the previously reported threshold for islet allografts  both pre- and posttransplant and have maintained full graft function beyond the initial one year of post-transplant follow-up care. Furthermore, none of the
Fig. 4. sCD30 levels as examined by both immunosuppressive protocol and eventual graft outcome. Solid bars — full graft function at 1 year post-transplant; open bars — partial or no graft function at 1 year post-transplant. The early increase in sCD30 levels in recipients receiving hOKT3γ-ala,ala in patients who result in partial or no graft function 1 year post-transplant: day 4–day 7 (a), day 28 (b), and day 90–day 120 (c). *** = p b 0.005. See Table 1 for recipient numbers within groups.
serum samples tested, including those from recipients who experienced graft rejection, had sCD30 levels as high as the upper thresholds achieved in the previous studies. Whether due to testing site, assay reagents, or patient subsets, the large amount of variability that exists in recipient sCD30 levels that may make it difﬁcult to draw conclusions based on this immunological factor alone. Recipients in this study who exhibited a large reduction in sCD30 levels post-transplant relative to the pre-transplant level were more likely to have full graft function at one year follow-up, regardless of which of the three immunosuppressive protocols used. This indicates that it is a reduction in sCD30 levels relative to post-transplant that correlates with eventual graft function. Pelzl et al.  found that
K. Hire et al. / Transplant Immunology 23 (2010) 209–214
a reduction in sCD30 levels within the ﬁrst week post-transplant correlated with graft function . Other studies have also found a post-transplant reduction in sCD30 levels [10,19,24,25,27]. These studies noted that the correlation between sCD30 levels and allograft outcome was stronger at different time points (within days and up to one-month post-transplant) [10,19,24,25,27]. Our data concurs with these studies, suggesting that monitoring the reduction of sCD30 levels in islet allograft recipients post-transplant may be predictive of eventual graft function. However, monitoring of the reduction of sCD30 levels beyond the ﬁrst week and through one-month posttransplant may be more indicative of eventual islet allograft outcome. Soluble CD30 levels may also be useful in tailoring immunosuppression. In a study of kidney transplant recipients, Schlaf et al.  speculated that the mode of action of the immunosuppressive therapy impacts the correlation between sCD30 levels and graft outcome. Higher pre-transplant sCD30 levels correlated with increased graft failure. However, treatment with anti-lymphocyte antibodies as induction therapy resulted in increased graft survival in those “high sCD30” recipients, indicating the potential to tailor immunosuppression to improve graft function in recipients considered at-risk by pre-transplant sCD30 monitoring. The three immunosuppressive protocols used by recipients in this study may have also have affected the degree of change in sCD30 levels observed post-transplant relative to pre-transplant. hOKT3γ-ala,ala, an anti-CD3 monoclonal antibody, is a potent T-cell depletion agent. However, it has also been shown to activate T cells as they are depleted. This period of early T-cell activation would explain the increase in sCD30 levels observed early post-transplant (days 4–7) in recipients receiving hOKT3γ-ala,ala as sCD30 is cleaved from CD30 expressed by T cells during T-cell activation. After the initial depletion effects of hOKT3γala,ala induction treatment, sCD30 returned to near baseline levels at day 28 (Fig. 3b). ATG, on the other hands, may result in T-cell depletion through cell lysis without activation, and therefore would not be expected to cause an increase in serum sCD30, as conﬁrmed by our data. Daclizumab binds to the IL-2 receptor located on T cells, preventing T-cell activation without depletion, and also would not be expected to result in T-cell activation and a subsequent increase in sCD30 levels, as seen in Fig. 4. In considering the study results, it should be noted that the use of retrospective data is inherently limited yet provides useful information regarding potential markers that can be beneﬁcial in predicting immune rejection and graft outcome. Additionally, the small sample size presented here prevented calculation of the sensitivity, speciﬁcity, and positive predictive value of changes in sCD30 values. These factors should, therefore, be considered prior to extrapolating the results to a broader population of islet and/or solid organ transplant recipients. Prospective study of a larger population of islet transplant recipients is required prior to making speciﬁc recommendations on the use of serial sCD30 monitoring to measure rejection processes affecting function of islet allograft transplants. The ﬁndings in this study differ from previously established studies examining sCD30 levels as a predictive marker of allograft (kidney) rejection  in that we did not ﬁnd a correlation between pretransplant CD30 levels and graft outcome. It is possible that the type of graft involved, i.e. an islet allograft versus solid organ transplantations, may have affected the predictive nature of sCD30 levels. Moreover, use of immunosuppressive drugs differs between kidney transplant and islet transplant and we show that immunosuppressive drugs change levels of CD30. It is likely that a combination of the graft and immunosuppressive drugs contributed to our ﬁndings which do not concur with reported results in kidney transplant. Therefore, rather than deﬁning speciﬁc sCD30 values for use as indicators of graft failure, it is potentially more informative to evaluate the relative changes in sCD30 levels pre- and post-transplant for each individual recipient. This ﬁnding conﬁrms the results of Altermann et al.  who discuss individualized evaluation of post-transplant
sCD30 levels as a biomarker considered in conjunction with other concomitant disease which may affect post-transplant immunological reactivity. 6. Conclusions In conclusion, this study demonstrates that a relative reduction in sCD30 levels post-transplant is indicative of full graft function at one year post-transplant in recipients of islet allografts. Pre-transplant screening combined with post-transplant monitoring and subsequent adjustment of immunosuppressive therapies, may increase graft function and prevent loss of graft function in high-risk islet allograft recipients. Acknowledgements This study was support by grants from the National Institutes of Health (National Institute for Diabetes, Digestive and Kidney Diseases, DK56963) and the Juvenile Diabetes Research Foundation (JRDF #42008-386), and with support from the Richard M. Schulze Family Foundation. References  Schlaf G, Altermann WW, Rothhoff A, Seliger B. Soluble CD30 serum level — an adequate marker for allograft rejection of solid organs? Histol Histopathol 2007;22:1269–79.  Caligaris-Cappio F, Bertero MT, Converso M, Stacchini A, Vinante F, Romagnani S, et al. Circulating levels of soluble CD30, a marker of cells producing Th2-type cytokines, are increased in patients with systemic lupus erythematosus and correlate with disease activity. Clin Exp Rheumatol 1995;13:339–43.  Makhseed M, Raghupathy R, Azizieh F, Farhat R, Hassan N, Bandar A. Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions. Hum Reprod 2000;15:2011–7.  Pizzolo G, Vinante F, Nadali G, Krampera M, Morosato L, Chilosi M, et al. High serum level of soluble CD30 in acute primary HIV-1 infection. Clin Exp Immunol 1997;108:251–3.  Fattovich G, Vinante F, Giustina G, Morosato L, Alberti A, Ruol A, et al. Serum levels of soluble CD30 in chronic hepatitis B virus infection. Clin Exp Immunol 1996;103: 105–10.  Leonard C, Tormey V, Faul J, Burke CM, Poulter LW. Allergen-induced CD30 expression on T cells of atopic asthmatics. Clin Exp Allergy 1997;27:780–6.  Cinti P, Pretagostini R, Arpino A, Tamburro ML, Mengasini S, Lattanzi R, et al. Evaluation of pretransplant immunologic status in kidney-transplant recipients by panel reactive antibody and soluble CD30 determinations. Transplantation 2005;79:1154–6.  Heinemann FM, Rebmann V, Witzke O, Philipp T, Broelsch CE, Grosse-Wilde H. Association of elevated pretransplant sCD30 levels with graft loss in 206 patients treated with modern immunosuppressive therapies after renal transplantation. Transplantation 2007;83:706–11.  Langan LL, Park LP, Hughes TL, Irish A, Luxton G, Witt CS, et al. Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival. Am J Transplant 2007;7:847–56.  Sengul S, Keven K, Gormez U, Kutlay S, Erturk S, Erbay B. Identiﬁcation of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation. Transplantation 2006;81:1216–9.  Susal C, Pelzl S, Dohler B, Opelz G. Identiﬁcation of highly responsive kidney transplant recipients using pretransplant soluble CD30. J Am Soc Nephrol 2002;13: 1650–6.  Susal C, Pelzl S, Simon T, Opelz G. Advances in pre- and posttransplant immunologic testing in kidney transplantation. Transplant Proc 2004;36:29–34.  Wang D, Wu GJ, Wu WZ, Yang S, Chen J, Wang H, et al. Pre- and post-transplant monitoring of soluble CD30 levels as predictor of acute renal allograft rejection. Transpl Immunol 2007;17:278–82.  Yang JL, Hao HJ, Zhang B, Liu YX, Chen S, Na YQ. Level of soluble CD30 after kidney transplantation correlates with acute rejection episodes. Transplant Proc 2008;40: 3381–3.  Susal C, Pelzl S, Opelz G. Strong human leukocyte antigen matching effect in nonsensitized kidney recipients with high pretransplant soluble CD30. Transplantation 2003;76:1231–2.  Vaidya S, Partlow D, Barnes T, Gugliuzza K. Pretransplant soluble CD30 is a better predictor of posttransplant development of donor-speciﬁc antibodies and acute vascular rejection than panel reactive antibodies. Transplantation 2006;82:1606–9.  Shah AS, Leffell MS, Lucas D, Zachary AA. Elevated pretransplantation soluble CD30 is associated with decreased early allograft function after human lung transplantation. Hum Immunol 2009;70:101–3.  Truong DQ, Darwish AA, Gras J, Wieers G, Cornet A, Robert A, et al. Immunological monitoring after organ transplantation: potential role of soluble CD30 blood level measurement. Transpl Immunol 2007;17:283–7.
K. Hire et al. / Transplant Immunology 23 (2010) 209–214
 Cervelli C, Fontecchio G, Scimitarra M, Azzarone R, Famulari A, Pisani F, et al. Evaluation of serum sCD30 in renal transplantation patients with and without acute rejection. Transplant Proc 2009;41:1159–61.  Dong W, Shunliang Y, Weizhen W, Qinghua W, Zhangxin Z, Jianming T, et al. Prediction of acute renal allograft rejection in early post-transplantation period by soluble CD30. Transpl Immunol 2006;16:41–5.  Giannoli C, Bonnet MC, Perrat G, Houillon A, Reydet S, Pouteil-Noble C, et al. High pretransplantation soluble CD30 levels: impact in renal transplantation. Transplant Proc 2007;39:2574–5.  Kim MS, Kim HJ, Kim SI, Ahn HJ, Ju MK, Kim HJ, et al. Pretransplant soluble CD30 level has limited effect on acute rejection, but affects graft function in living donor kidney transplantation. Transplantation 2006;82:1602–5.  Kovac J, Arnol M, Vidan-Jeras B, Bren AF, Kandus A. Does pretransplant soluble CD30 serum concentration affect deceased-donor kidney graft function 3 years after transplantation? Transplant Proc 2008;40:1357–61.  Nafar M, Farrokhi F, Vaezi M, Entezari A, Pour-Reza-Gholi F, Firoozan A, et al. Pretransplant and post-transplant soluble CD30 for prediction and diagnosis of acute kidney allograft rejection. Int Urol Nephrol 2009;41:687–93.  Platt RE, Wu KS, Poole K, Newstead CG, Clark B. Soluble CD30 as a prognostic factor for outcome following renal transplantation. J Clin Pathol 2009;62:662–3.  Slavcev A, Honsova E, Lodererova A, Pavlova Y, Sajdlova H, Vitko S, et al. Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft. Transpl Immunol 2007;18:22–7.  Matinlauri I, Hockerstedt K, Isoniemi H. High serum soluble CD30 does not predict acute rejection in liver transplant patients. Transplant Proc 2006;38:3601–4.  Spiridon C, Hunt J, Mack M, Rosenthal J, Anderson A, Eichhorn E, et al. Evaluation of soluble CD30 as an immunologic marker in heart transplant recipients. Transplant Proc 2006;38:3689–91.
 Spiridon C, Nikaein A, Lerman M, Hunt J, Dickerman R, Mack M. CD30, a marker to detect the high-risk kidney transplant recipients. Clin Transpl 2008;22:765–9.  Bellin MD, Kandaswamy R, Parkey J, Zhang HJ, Liu B, Ihm SH, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant 2008;8:2463–70.  Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 2005;293:830–5.  Hering BJ, Kandaswamy R, Harmon JV, Ansite JD, Clemmings SM, Sakai T, et al. Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 2004;4:390–401.  Campbell PM, Senior PA, Salam A, Labranche K, Bigam DL, Kneteman NM, et al. High risk of sensitization after failed islet transplantation. Am J Transplant 2007;7: 2311–7.  Saini D, Ramachandran S, Nataraju A, Benshoff N, Liu W, Desai N, et al. Activated effector and memory T cells contribute to circulating sCD30: potential marker for islet allograft rejection. Am J Transplant 2008;8:1798–1808.  Pelzl S, Opelz G, Daniel V, Wiesel M, Susal C. Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection. Transplantation 2003;75:421–3.  Altermann W, Schlaf G, Rothhoff A, Seliger B. High variation of individual soluble serum CD30 levels of pre-transplantation patients: sCD30 a feasible marker for prediction of kidney allograft rejection? Nephrol Dial Transplant 2007;22: 2795–9.