Long-term survival in a patient with AL amyloidosis after cardiac transplantation followed by autologous stem cell transplantation.
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Adult↗
Biomedical subjects
T J Dengler
Publications and source records attributed to T J Dengler.
Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy.
Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low-dose CNI therapy. Thirty-nine patients with renal failure on low-dose cyclosporine A (CsA) were studied (62.9 +/- 8.7 years, five female, 8.2 +/- 4.3 years posttransplant, serum creatinine: 1.9 +/- 0.3 mg/dL, calculated GFR (cGFR): 48.2 +/- 18.3 mL/min, CsA C0 level: 64.0 +/- 19.9 ng/mL). All patients had been treated with low-dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7-3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low-dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 +/- 0.15 to 1.67 +/- 0.13 mg/dL, cGFR: 48.5 +/- 21.4 to 61.7 +/- 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantation who are at low risk of rejection, CNI-free rapamycin-based immunosuppression improves cGFR even in those already receiving low-dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.
Adult↗
The Eurotransplant High-Urgency Heart Transplantation Program: an option for patients in acute heart failure?
OBJECTIVE: The Eurotransplant High-Urgency (HU) Heart Transplantation Program allows urgent heart transplants to be carried out in rapidly deteriorating patients with acute-to-chronic heart failure on the elective waiting list. But do the results of HU heart transplantation justify performing primary heart transplantation in these critically ill patients and offer an acceptable outcome? METHODS: Between 2000 and 2004, 64 heart transplantations (HTx) (32 elective and 32 HU-HTx) were performed in our department. After having been accepted in an auditing process based on HU criteria, intensive care patients in NYHA functional class IV (cardiac index 1.7 l/min/qm BS), in end-organ failure (creatinine 1.5 mg/dl), and with catecholamine dependence (dobutamine 8 microg/kg/min), are given priority with respect to organ allocation, and their data were compared to data from elective patients from the same period. RESULTS: HU requests were accepted in 97 % of cases. Two requests were not accepted, and both patients with contraindications for assist device implantation died within one week. The HU patients were 100 % in NYHA class IV, 93 % of the elective patients were in NYHA class III. Waiting time on the HU list was 13 days, and 7 of these patients died before HTx. Following heart transplantation, survival rates at 30 days and at one year of the HU group were 88 % and 85 % versus 94 % and 93 % in the elective group. CONCLUSIONS: This study shows that end-stage heart failure patients in the HU program can be transplanted primarily with good results if an organ is available in time. We are still in the position where the HU program only manages the organ shortage; there are still too many patients on the waiting list who die before receiving a donor organ.
Acute Disease↗
Interstitial fibrosis in the heart: differences in extracellular matrix proteins and matrix metalloproteinases in end-stage dilated, ischaemic and valvular cardiomyopathy.
AIMS: To investigate whether or not there are differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs) in end-stage heart failure underlying different cardiomyopathies. METHODS AND RESULTS: Thirty-nine explanted human hearts were investigated: 15 with dilated cardiomyopathy (DCM), 17 with ischaemic cardiomyopathy (ICM) and seven with valvular cardiomyopathy (VCM). Transmural samples from four different sites were investigated. Frozen sections were processed for immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities were determined. All ECM components were expressed more frequently in DCM than in ICM. Comparing ICM with VCM, all proteins were found more frequently in VCM than in ICM except for type III collagen, which was significantly more frequent in ICM. Comparing DCM and VCM, VCM showed significantly higher volume densities for type III collagen and laminin. MMPs showed only slight variations between the cardiomyopathies. CONCLUSION: The distribution of ECM proteins differs between DCM, ICM and VCM, which suggests that they can be morphologically discriminated by interstitial fibrosis, especially by their expression of matrix proteins.
Adult↗
Raised B-type natriuretic peptide predicts implantable cardioverter-defibrillator therapy in patients with ischaemic cardiomyopathy.
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Biomarkers↗
Detection of cardiac allograft rejection by real-time PCR analysis of circulating mononuclear cells.
BACKGROUND: Detection of cardiac allograft rejection is based on the histological examination of endomyocardial biopsies (EMB). We have explored the possibility of whether graft rejection could be detected by characteristic gene expression patterns in peripheral blood mononuclear cells (PBMC) of heart-transplant recipients. METHODS: The study included 58 blood samples of 44 patients. On the day of EMB, mononuclear cells were isolated from peripheral blood, and gene expression was measured by quantitative real-time PCR. Thirty-nine parameters, including cytokine and chemokine genes were analyzed. Gene expression results were correlated with histological assessment of concomitant evaluated EMB according to International Society for Heart and Lung Transplantation (ISHLT) nomenclature. RESULTS: Gene expression of perforin, CD95 ligand, granzyme B, RANTES, CXCR3, COX2, ENA 78 and TGF-beta1 was significantly different in PBMC of patients with mild to moderate degrees of allograft rejection (> or =grade 2) compared with patients exhibiting no or minor forms of rejection ( or =grade 2 vs. <grade 2 with a sensitivity of 84% and a specificity of 82% as assessed by receiver operating characteristic analysis. CONCLUSION: Quantitative analysis of gene expression in PBMC may be a valuable tool for non-invasive diagnosis of allograft rejection and may allow further insight in the biological process of graft rejection.
Antigens, Surface↗
Extended experience and subgroup analysis using cardiac troponin T for rejection monitoring after heart transplantation.
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Adolescent↗
Do cytokines enable risk stratification to be improved in NYHA functional class III patients? Comparison with other potential predictors of prognosis.
AIMS: Elevated plasma levels of proinflammatory cytokines have been reported in patients with congestive heart failure. The purpose of this study was to assess whether cytokines improve risk stratification in a homogeneous group of NYHA class III patients with a left ventricular ejection fraction <40%. METHODS AND RESULTS: Plasma concentrations of big endothelin, tumour necrosis factor alpha, interleukins -1, -6, -10 and -12, sCD14 and GM-CSF were measured by ELISA in 91 NYHA III patients [mean (SD) age: 55 (10) years, 69% male, 34% coronary artery disease, 66% dilated cardiomyopathy] with a left ventricular ejection fraction and a peak oxygen uptake (peak VO2) of 19 (9)% and 12.1 (3.6) ml x min(-1) x kg(-1), respectively. During follow-up [22 (13) months], 31 patients (34%) died due to cardiovascular causes. In non-survivors, interleukin-6 was twice as high as in survivors [12.8 (16.9) pg x ml(-1)vs 5.6(5.3) pg x ml(-1), P<0.003], whereas plasma concentrations of the other cytokines showed no significant differences. Concerning long-term survival (> or =1 year), multivariate Cox regression analysis revealed an independent prognostic power for interleukin-6, which was further improved by combining with left ventricular ejection fraction and peak VO2, while for short-term survival (up to 6 months) interleukin-6 did not allow risk stratification. CONCLUSION: In NYHA class III patients, plasma concentrations of interleukin-6 are predictive of long-term survival. However, its value may be limited for clinical decision-making for cardiac transplantation (short-term survival).
Aged↗
Troponin T concentrations 72 hours after myocardial infarction as a serological estimate of infarct size.
BACKGROUND: After acute myocardial infarction, the structural protein T is released considerably longer than cytosolic creatine kinase (CK), CK MB isoenzyme (CK-MB), or lactate dehydrogenase (LDH) and late troponin T release (> 48 hours after onset of chest pain) appears to be less affected by early coronary reperfusion. OBJECTIVE: To investigate the precision of a single measurement of circulating troponin T concentrations 72 hours after onset of chest pain compared with standard scintigraphic and enzymatic estimates of myocardial infarct size. METHODS: Quantitative single photon emission computed tomography thallium-201 scintigraphy at rest was performed in 37 patients 2-3 weeks after myocardial infarction (group 1: 14 patients without early coronary reperfusion; group 2: 23 patients with early reperfusion achieved by thrombolytic therapy, by percutaneous transluminal coronary angioplasty, or by both). RESULTS: In both groups, the number of myocardial segments with abnormal thallium-201 uptake indicating the individual extent of irreversible myocardial damage correlated significantly with the troponin T concentrations 72 hours after infarction as well as with peak concentrations of CK, CK-MB, and LDH. CONCLUSION: The data show that a single measurement of circulating troponin T 72 hours after onset of chest pain--independent of reperfusion--is superior for the estimation of myocardial infarct size to measurement of peak CK, CK-MB, or LDH, which require serial determinations and depend on coronary reperfusion.
Adult↗
Human vascular endothelial cells stimulate a lower frequency of alloreactive CD8+ pre-CTL and induce less clonal expansion than matching B lymphoblastoid cells: development of a novel limiting dilution analysis method based on CFSE labeling of lymphocytes.
We have previously shown that human endothelial cells (EC) are less efficient than professional APC, e.g., B lymphoblastoid cells (BLC), at stimulating allogeneic CD8(+) T cells to develop into CTL. In this study we describe FACS-based limiting dilution analyses using the dilution of the intracellular dye CFSE as an indicator of CD8(+) T cell alloactivation and expansion with significantly increased sensitivity compared with conventional, cytotoxicity-based assays. In addition, this assay permits the relative size of clonal CTL populations that are generated in individual CD8(+) T cell cultures to be determined (clonal burst size). We have applied this method to quantitatively compare the generation of CTL at the clonal level following stimulation of allogeneic CD8(+) T cells by either BLC or HUVEC derived from the same donor. CD8(+) T cells expanded by allostimulation were identified as CD8(+), CFSE(low) cells and were categorized as CTL by the expression of intracellular perforin and IFN-gamma. Precursor frequencies for EC-stimulated CTL were 5- to 40-fold (mean, 7.5-fold) lower compared with BLC-stimulated CTL (p < 0.01). Concomitantly, the average clonal burst sizes in EC-stimulated CTL cultures were significantly smaller than those in conventional CTL cultures, primarily due to the occurrence of some very large clone sizes exclusively with BLC stimulation. Although EC-stimulated CTL were generated only from the memory subset of CD8(+) T cells, BLC-stimulated very large burst sizes of CTL were observed from both naive and memory CD8(+) T cell precursors. These data establish that both a lower frequency of reactive precursors and more limited clonal expansion, but not regulatory T cells, contribute to the reduced capacity of EC to promote alloreactive CTL differentiation compared with that of professional APC.
Antigens, CD↗
Systolic and diastolic properties and myocardial blood flow in the heterotopically transplanted rat heart during acute cardiac rejection.
The aim of the study was to characterize the course of systolic and diastolic function, myocardial blood flow, and histologic changes during acute rejection in a model of heterotopic transplantation in rats. For this purpose isogenic Lewis-to-Lewis and allogenic DA (Dark Agouti)-to-Lewis rat cardiac transplants were studied 1 hour and 1, 3, and 5 days, respectively, after heterotopic intraabdominal transplantation. Myocardial tissue blood flow (MBF) was assessed by the hydrogen-clearance method. An implanted balloon was used to measure pressure-volume relations in the transplanted heart. Myocardial water content was determined at the end of the experiments, and histologic examinations were performed. The MBF recovered during the first day postoperatively in both groups and decreased again in the allogenic group after 3 and 5 days (p < 0.05); it remained stable in the isogenic group. Myocardial relaxation was already prolonged in the allogenic group after 3 days and deteriorated further. Left ventricular end-diastolic pressure progressively increased in the allogenic group, whereas it remained unchanged in the isogenic group up to 5 days. After recovery from ischemia, the left ventricular peak systolic pressure was stable in the isogenic group for the entire further observation period, but it significantly decreased in the allogenic group after 5 days (p < 0.05). Myocardial water content showed a significant increase in the allogenic group compared to that in the isogenic group after 5 days. In the allogenic group histologic examination confirmed mild to moderate rejection after 3 days and severe acute rejection after 5 days. Thus, after recovery from ischemia, mild to moderate cardiac rejection was associated with reduced MBF and impaired relaxation. In a typical sequence, generation of edema and impaired diastolic compliance were terminally followed by systolic dysfunction during severe rejection.
Animals↗
Ex vivo evaluation of PBMNCs collected with a new cell separator.
BACKGROUND: This study reports on an evaluation of the ability of a cell separator (Amicus, Baxter Healthcare) and the integral MNC computer software program to collect a variety of MNC subsets. The collection efficiency (CE) of the Amicus for these MNC subsets was compared to that of another cell separator (CS-3000 Plus, Baxter). The collected MNCs were also assayed ex vivo to determine if these cells remained functional. STUDY DESIGN AND METHODS: Healthy volunteer blood donors were recruited to provide PBMNCs for the isolation of CD3+, CD4+, CD8+, CD19+, NK, and gammadelta+ cells and monocytes. Cells were collected with an Amicus (test arm; n = 16) or a CS-3000 Plus (control arm; n = 11) cell separator. Cells were counted on a flow cytometer and CEs were calculated. For functional studies, the Amicus-collected MNC data were compared to CS-3000 Plus historical data. Functional studies performed included surface antigen expression assays (CD8+), proliferation assays (CD4+ and CD8+ cells), NK cytotoxicity assays for K562 and HUVE cells, and E-selectin induction on endothelial cells through NK+ contact dependency. Dendritic cells (DCs) were generated from CD34+ cells collected on the Amicus, positively selected by the use of antibody-bound, magnetic bead technology, and then cultured ex vivo with a combination of growth factors to generate the DCs. RESULTS: CEs were higher on the Amicus than on the CS-3000 Plus for CD3+ (68 vs. 54%), CD4+ (70 vs. 56%), CD8+ (68 vs. 52%), and CD19+ (60 vs. 48%) cells (p<0.05). For the two separators, CEs were equivalent for monocytes, NK+, and gammadelta+ cells. The Amicus separator collected significantly fewer platelets than did the CS-3000 Plus (p<0.00001). CD4+, CD8+, and NK cells proliferated normally. NK cells appropriately stimulated E-selectin expression on endothelial cells. Culture-generated DCs obtained by using Amicus-collected CD34+ cells expressed appropriate cell surface markers. CONCLUSION: The Amicus separator is acceptable for the collection of PBMNC subsets. The device collects CD3+, CD4+, CD8+, and CD19+ T- and B-cell subsets with greater efficiency and collects MNCs with significantly fewer contaminating platelets than does the CS-3000 Plus. Cells collected on the Amicus are suitable for use in a variety of research and clinical immunobiologic studies.
Blood Donors↗
Human vascular endothelial cells stimulate memory but not naive CD8+ T cells to differentiate into CTL retaining an early activation phenotype.
Endothelial cell (EC)-selective alloreactive CTL may mediate alloimmune vascular injury. In the present study, EC-selective CTL were generated in cocultures of purified human CD8+ T cells with allogeneic EC and were compared with conventional CTL against corresponding B lymphoblastoid cells (BLC). EC caused activation and expansion of memory but not naive CD8+ T cells, which differentiated into EC-selective CTL that retained high surface expression of CD69, CD25, and CD62L and displayed low intracellular perforin content. In contrast, BLC-stimulated CTL could be generated from naive or memory CD8+ T cells and showed a more mature phenotype (low CD69, CD25, and CD62L with higher levels of perforin). The expansion of alloreactive T cells by EC stimulation was 5- to 20-fold less effective than in corresponding BLC-stimulated cultures, accounting for a reduction in the assayable cytotoxicity of individual microcultures. In these IL-2-supplemented cocultures, no effect on CTL generation or phenotype was observed by mAb blocking of costimulation provided by LFA-3, ICAM-1, or CD40, by addition of comitogenic anti-CD28 mAb, or by preactivation of EC with CD40 ligand. Cyclosporine inhibited CTL expansion and cytotoxicity similarly in both EC- and BLC-stimulated cultures but did not affect the phenotype of those CTL that did emerge. This study extends the characterization of endothelium as an immunoregulatory cell type distinct from conventional APC and may explain why graft rejection within the arterial intima, an anatomic compartment in which EC may be the primary type of APC, is separable from rejection in the graft parenchyma.
B-Lymphocytes↗
Cytoprotection of human umbilical vein endothelial cells against apoptosis and CTL-mediated lysis provided by caspase-resistant Bcl-2 without alterations in growth or activation responses.
Graft endothelial cells are primary targets of host CTL-mediated injury in acute allograft rejection. As an in vitro trial of gene therapy to reduce CTL-mediated endothelial injury, we stably transduced early passage HUVEC with a caspase-resistant mutant form (D34A) of the anti-apoptotic gene Bcl-2. Bcl-2 transductants were compared with HUVEC transduced in parallel with an enhanced green fluorescent protein (EGFP) gene. Both transduced HUVEC have equivalent growth rates in complete medium and both show contact inhibition of growth. However, compared with EGFP-transduced HUVEC, the Bcl-2-transduced cells are resistant to the apoptotic effects of serum and growth factor withdrawal and are also resistant to the induction of apoptosis by staurosporine or by ceramide, with or without TNF. Transduced Bcl-2 did not reduce TNF-mediated NF-kappaB activation or constitutive expression of class I MHC molecules. HUVEC expressing D34A Bcl-2 were significantly more resistant to lysis by either class I-restricted alloreactive or PHA-redirected CTL than were HUVEC expressing EGFP. We conclude that transduction of graft endothelial cells with D34A Bcl-2 is a possible approach for reducing allograft rejection.
Apoptosis↗
Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1beta.
BACKGROUND: Infection with human cytomegalovirus (HCMV) has been associated with vascular disease processes such as vascular allograft rejection, transplantation vasculopathy, restenosis after angioplasty, and native atherosclerosis. To elucidate underlying pathomechanisms, the effect of acute HCMV infection on the expression of pro-inflammatory adhesion molecules on human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (hvSMC) was examined. METHODS AND RESULTS: Cells were infected in vitro with clinical strains of HCMV and the resulting changes in adhesion molecule expression were quantified by histology and flow cytometric analysis. On HUVEC, surface expression of vascular cell adhesion molecule-1 and E-selectin was induced de novo on HCMV infection and intercellular adhesion molecule-1 expression was increased by >200%. On hvSMC, intercellular adhesion molecule-1 surface expression induced de novo, although vascular cell adhesion molecule-1 and E-selectin were not changed. Expression of major histocompatibility complex (MHC) class II, lymphocyte-function associated antigen 3 (LFA-3; CD58), and CD40 was not altered by HCMV infection in either cell type. In partially infected cultures, up-regulation of surface molecules also occurred on noninfected cells, suggesting a paracrine mechanism via a soluble factor. Expression of surface molecules could be enhanced in noninfected HUVEC and hvSMC by incubation with virus-free conditioned supernatant from HCMV-infected cells or by coincubation in transwells with infected cells. The responsible agent could be identified as IL- interleukin- (IL) 1beta by detection of de novo secretion of IL-1beta by HCMV-infected cells and by prevention of adhesion molecule up-regulation after addition of an IL-1-converting enzyme inhibitor or IL-1 receptor antagonist. Surface molecule up-regulation could be suppressed by UV inactivation of virus, but not by treatment of cell cultures with inhibitors of viral replication (ganciclovir). CONCLUSION: We propose that HCMV infection induces IL-1beta release and subsequent up-regulation of pro-inflammatory adhesion molecules on noninfected neighboring cells through a paracrine mechanism. This may lead to local potentiation of the inflammatory effects of HCMV infection, not amenable to current therapeutic antiviral strategies.
Cell Adhesion Molecules↗
[Long-term management after heart transplantation--an assessment of current status].
Due to an improvement of results after heart transplantation, there is a continuously growing number of long-term surviving patients. Aimed at a characterization of established diagnostic and therapeutic protocols, the Working Group of Thoracic Organ Transplantation within the German Society of Cardiology performed a survey among all German heart transplantation centers. Based on the experience of 1,500 patients, the clinical relevance as well as approaches for prevention and treatment of rejection, infection, cardiac allograft vasculopathy, malignancy, hypertension, renal insufficiency, and quality of life were assessed by a questionnaire. As a result, a time dependency of expected complications could clearly be shown. While early after HTX acute rejection and infection episodes were judged as clinically important, later on cardiac allograft vasculopathy, malignancy, and renal insufficiency predominate as relevant complications. This spectrum was reflected by a differentiated diagnostic protocol (early after HTX more frequent diagnostic procedures for rejection and infection, later intensified examinations to identify cardiac allograft vascular disease and malignancy) as well as by different intensities of immunosuppression and concomittant medication. Regarding further improvement of survival rates and quality of life, future clinical and scientific activities should be focused on the prevention of late complications after heart transplantation.
Aftercare↗
Vaccination against tick-borne encephalitis under therapeutic immunosuppression. Reduced efficacy in heart transplant recipients.
Patients after organ transplantation are at an increased risk of microbial infections and might benefit from active vaccination. Due to therapeutic immunosuppression the efficacy of immunizations is, however, reduced and difficult to predict. Efficacy of vaccination against tick-borne encephalitis (TBE) using an abbreviated immunization schedule was compared in 31 heart transplant recipients (age: 54.5 +/- 11.5 years, mean time after transplantation: 53.5 +/- 23.7 months) under cyclosporine-based immunosuppression and 29 controls. TBE vaccination was well tolerated by the transplant recipients; spectrum and frequency of adverse events were similar to controls. In the transplant patients, seroconversion rate (35% versus 100%; p < 0.001) and the geometric mean of post-vaccinal antibody titres (0.98 (SF: 2.3) U/ml versus 5.46 (2.2) U/ml; p < 0.001) were markedly reduced in comparison to the control group. No clinical or demographic predictors of vaccination success could be established in the transplant patients. Due to the limited efficacy, TBE vaccination cannot be recommended as a routine procedure in heart transplant recipients at risk of TBE virus infection. TBE vaccination may be performed safely in selected cases, but repeated titre controls to confirm vaccination success would be required.
Adult↗
Prolonged allograft survival but no tolerance induction by modulating CD28 antibody JJ319 after high-responder rat heart transplantation.
BACKGROUND: Allograft rejection depends on T cell immune responses requiring antigen recognition and costimulatory signals through accessory T cell receptors, including CD28. Inhibition of CD28 signaling with a CTLA-4-immunoglobulin (Ig) fusion protein has resulted in immunosuppression and occasional T cell anergy in mouse transplant models, but not in rats. Because this approach also inhibits a potentially tolerizing signal through CTLA-4, selective blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance. METHODS: The effects of escalating doses of the rat CD28 monoclonal antibody JJ319 on allograft survival were studied after vascularized heterotopic heart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by flow cytometry. RESULTS: CD28 antibody JJ319 markedly prolonged cardiac graft survival compared with untreated controls (7 days, range: 6-8). A strictly dose-dependent increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p <0.001) after the administration of 8 x 1 mg JJ319 i.p. (days -1 to +6 before/after transplantation). However, indefinite graft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 receptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed significantly reduced responses to activation. CONCLUSIONS: CD28 antibody JJ319 induces profound immunosuppression after rat heart transplantation, however without development of transplant tolerance. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, there are no qualitative or quantitative differences to the treatment with CTLA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere. Thus, a CD28-modulating approach seems not to allow therapeutic exploitation of a tolerizing signal delivered by CTLA-4 but may still be clinically applicable, especially in combined immune interventions.
Abatacept↗