scholarly journals C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Robin Schmitz ◽  
Zachary W. Fitch ◽  
Paul M. Schroder ◽  
Ashley Y. Choi ◽  
Miriam Manook ◽  
...  
Keyword(s):  
Graft Survival ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
B Cell Activation ◽  
Kidney Transplant Recipients ◽  
Allograft Survival ◽  
Primate Model ◽  
Antibody Mediated Rejection ◽  
Complement Component C3 ◽  
Antibody Levels

AbstractSensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury.

scholarly journals Outcomes of Kidney Transplant Recipients with Sickle Cell Disease: An Analysis of the 2000–2019 UNOS/OPTN Database

2021 ◽  
Vol 10 (14) ◽  
pp. 3063
Author(s):  
Napat Leeaphorn ◽  
Charat Thongprayoon ◽  
Pradeep Vaitla ◽  
Panupong Hansrivijit ◽  
Caroline C. Jadlowiec ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Survival ◽  
Patient Survival ◽  
Transplant Recipients ◽  
Cell Disease ◽  
Kidney Transplant Recipients ◽  
Allograft Survival ◽  
End Stage Kidney Disease ◽  
Kidney Recipients ◽  
End Stage

Background: Lower patient survival has been observed in sickle cell disease (SCD) patients who go on to receive a kidney transplant. This study aimed to assess the post-transplant outcomes of SCD kidney transplant recipients in the contemporary era. Methods: We used the OPTN/UNOS database to identify first-time kidney transplant recipients from 2010 through 2019. We compared patient and allograft survival between recipients with SCD (n = 105) vs. all other diagnoses (non-SCD, n = 146,325) as the reported cause of end-stage kidney disease. We examined whether post-transplant outcomes improved among SCD in the recent era (2010–2019), compared to the early era (2000–2009). Results: After adjusting for differences in baseline characteristics, SCD was significantly associated with lower patient survival (HR 2.87; 95% CI 1.75–4.68) and death-censored graft survival (HR 1.98; 95% CI 1.30–3.01), compared to non-SCD recipients. The lower patient survival and death-censored graft survival in SCD recipients were consistently observed in comparison to outcomes of recipients with diabetes, glomerular disease, and hypertension as the cause of end-stage kidney disease. There was no significant difference in death censored graft survival (HR 0.99; 95% CI 0.51–1.73, p = 0.98) and patient survival (HR 0.93; 95% CI 0.50–1.74, p = 0.82) of SCD recipients in the recent versus early era. Conclusions: Patient and allograft survival in SCD kidney recipients were worse than recipients with other diagnoses. Overall SCD patient and allograft outcomes in the recent era did not improve from the early era. The findings of our study should not discourage kidney transplantation for ESKD patients with SCD due to a known survival benefit of transplantation compared with remaining on dialysis. Urgent future studies are needed to identify strategies to improve patient and allograft survival in SCD kidney recipients. In addition, it may be reasonable to assign risk adjustment for SCD patients.

scholarly journals Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients

2020 ◽  
Author(s):  
Renata Varnaitė ◽  
Marina García ◽  
Hedvig Glans ◽  
Kimia T. Maleki ◽  
John Tyler Sandberg ◽  
...  
Keyword(s):  
B Cell ◽  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
B Cell Activation ◽  
Immunological Parameters ◽  
Antibody Secreting Cell ◽  
Antibody Levels

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 patients during the acute phase of infection. Lastly, we showed that interleukin 6 (IL-6) and C-reactive protein (CRP) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 and CRP could be used to predict COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.

P1670GLOMERULAR C4D IN POST-TRANSPLANT IG-A GLOMERULONEPHRITIS IS ASSOCIATED WITH DECREASED ALLOGRAFT SURVIVAL

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Željko Kikić ◽  
Haris Omic ◽  
Georg A Böhmig ◽  
Nicolas Kozakowski ◽  
Michael Eder
Keyword(s):  
Graft Survival ◽  
Cox Regression ◽  
De Novo ◽  
Graft Loss ◽  
Allograft Survival ◽  
Cox Regression Analysis ◽  
Post Transplant ◽  
Antibody Mediated Rejection ◽  
Therapeutic Decisions ◽  
C4d Staining

Abstract Background and Aims Post transplant (pTX) glomerulonephritis (GN) is an important factor contributing to early and late allograft failure. De novo or recurrent IgA GN are the most frequent pTX-GN forms, however little is known about the optimal risk and therapeutic assessment. Recently, immunopathological evidence of glomerular C4d staining has been suggested as a prognostic tool in native glomerular kidney disease, in particular IgA GN. While peritubular capillary C4d is an accepted diagnostic criterion for antibody mediated rejection (ABMR), the role of glomerular C4d in pTX-GN is unkown. The primary hypothesis was that the finding of immunohistochemical glomerular C4d may be associated renal graft survival in post TX IgA GN. Method This large retrospective cohort study included all indication biopsies performed for cause in 885 kidney allografts from 1999-2006. Cases were screened for biopsy verified de novo or recurrent pTX-GN. GN cases were re-assessed by a single nephropathologist (NK). Primary endpoint was death-sensored graft survival followed until 01.01.2017. Results The prevalence of pTX-GN was 9.6% (n=85/885). De novo or recurrent IgA-GN was the most common pTX GN form with 40%. Of the 34 cases with pTX IgA GN, 27 had adequate material for interpretation of immunohistochemical glomerular C4d in the biopsy specimen. Eighteen of the 27 cases (66%) with pTx-IgA GN showed positive immunohistochemical C4d staining along glomerular capillary walls. There was no difference in renal function at biopsy or after one year comparing glomerular C4d positive vs. C4d negative pTX IgA GN. In univariate KM analysis glomerular C4d positive pTX-IgA GN showed significantly worse renal allograft survival rates (28%) compared to glomerular C4d negative pTX IgA GN (50%) or cases without GN (66%), p<0.001, respectively. In a multivariate Cox-Regression analysis including baseline covariates as well C4d+ABMR, Borderline lesion and TCMR, C4d+pTX IgA-GN remained independently associated with death censored graft-loss (HR 2.92, 95% CI 1.51-5.64, p=0.001). Conclusion Glomerular C4d staining in post transplant IgA glomerulonephritis is an independent risk factor for worse allograft survival and may provide a valuable risk assessment tool for prognostic and therapeutic decisions in post transplant glomerulonephritis.

scholarly journals P1738COULD ADDING BORTEZOMIB HAVE BENEFIT FOR ANTIBODY MEDIATED REJECTION AFTER KIDNEY TRANSPLANTATION?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Nooshin Dalili ◽  
Mohsen Nafar
Keyword(s):  
Kidney Transplantation ◽  
Intravenous Immunoglobulin ◽  
Kidney Transplant ◽  
Graft Survival ◽  
Vascular Inflammation ◽  
Standard Of Care ◽  
Kidney Transplant Recipients ◽  
Standard Regimen ◽  
Antibody Mediated Rejection ◽  
Protocol Biopsies

Abstract Background and Aims Antibody Mediated Rejection (ABMR) is a severe complication that frequently occurs after kidney transplantation. The present RCT designed to evaluate the role of adding Bortezomib to standard regimen with plasma exchange, intravenous immunoglobulin and Rituximab in treatment of AMR after kidney transplantation. Method 26 kidney transplant recipients (KTRs) with a biopsy proven diagnosis of AMR and positive DSA in a randomized clinical trial were compared: Thirteen KTRs treated with plasmapheresis, intravenous immunoglobulin and rituximab (PE-IVIG- RTX ) plus bortezomib versus 13 patients treated with standard of care regimen without bortezomib. We evaluated graft survival and DSA titer with MFI during a year after biopsy proven diagnosis. Results Statistical difference in graft survival between the two groups was noted: three out of 13 patients in the PE-IVIG-RTX group (23%) and 1/13 in the bortezomib group (7.5%) experienced loss of allograft function at a median time after diagnosis of 6 month and 12 month, respectively. DSA MFI titers 12 month after AMR diagnosis showed significant reducing slope in Bortezomib group. Regarding pathological changes micro vascular inflammation (glomerulitis + peritubular capillaritis score) reduced after PE-IVIG- RTX plus bortezomib in 7 out of 13 patients whom underwent protocol biopsies after treatment (53%) (Median score 3 in pre- treatment biopsy vs. 1 in post-treatment biopsy; P = 0.036). Conclusion Although DSA titer may not differ at 6 months after treatment of AMR between those who received standard regimen and those treated with adding Bortezomib, but at the end of one year patients treated with standard regimen plus Bortezomib reached lower MFI DSA titer. Adding Bortezomib to PE-IVIG- RTX for the treatment of AMR after kidney transplantation may enable clinicians to fight the DSA better and change the future of next generation of highly sensitized kidney transplant candidates.

scholarly journals The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Samantha J. Brunt ◽  
Silvia Lee ◽  
Lloyd D’Orsogna ◽  
Christine Bundell ◽  
Sally Burrows ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Longitudinal Analyses ◽  
B Cell Activation ◽  
Cell Recovery ◽  
Hiv Patients ◽  
Increased Risk ◽  
Antibody Titres ◽  
Humoral Responses ◽  
Antibody Levels

Objectives.Elevated humoral responses to cytomegalovirus (CMV) associate with increased risk of cardiovascular disease (CVD) in HIV patients on antiretroviral therapy (ART). To better understand the persistence of CMV humoral responses in relation to CVD, we determined trends in CMV antibody levels over the first 10 years on ART.Design.We describe longitudinal analyses of plasma from 13 HIV patients commencing ART with <210 CD4 T-cells/µL and 27 controls. Antibodies reactive with CMV (fibroblast lysate, gB and IE-1 antigens), EBV-VCA, and HIVgp41 were quantitated. B-cell activation was assessed via total IgG and sBAFF. Inflammation was assessed via sTNF-RI and sCD14.Results.Amongst CMV seropositive HIV patients, levels of antibody reactive with CMV(P=0.03)and EBV-VCA(P=0.02)peaked after 1 year on ART. Levels of total IgG, sCD14, and sTNF-RI declined to approximate those in controls after 10 years, but sBAFF(P=0.0002), EBV-VCA(P=0.001), and CMV(P=0.0004)antibodies remained elevated. A strong correlation between sBAFF and CMVgB antibody was seen at 10 years(R=0.93,  P=0.0009)and verified in a second cohort.Conclusions.CMV antibody titres peak on ART and remain high. A correlation between CMV antibody and sBAFF suggests a role for HIV-induced B-cell pathology that may affect its use as a marker of CMV burden.

scholarly journals The FCGR3A 158 V/V-genotype is associated with decreased survival of renal allografts with chronic active antibody-mediated rejection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicolle Litjens ◽  
Annemiek Peeters ◽  
Judith Kal-van Gestel ◽  
Mariska Klepper ◽  
Michiel Betjes
Keyword(s):  
Nk Cells ◽  
Graft Survival ◽  
Nk Cell ◽  
Cell Damage ◽  
Kidney Transplant Recipients ◽  
Antibody Mediated Rejection ◽  
Gamma Receptor ◽  
Cd16 Expression ◽  
Renal Allograft Loss ◽  
Allograft Loss

AbstractNatural killer (NK) cells express the Fc-gamma receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of chronic-active antibody mediated rejection (c-aABMR). The V/V-genotype of the FCGR3A 158 F/V polymorphism is associated with increased CD16 expression and cytotoxicity by NK cells. This study evaluated whether this genotype is associated with the diagnosis of c-aABMR and renal allograft loss. The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases (N = 133) compared to control kidney transplant recipients (N = 116, P = 0.65). The V-allele was associated with increased median fluorescence intensity (MFI) of CD16 by NK cells (MFI 3.5 × 104 versus 1.3 × 104 for V/V and F/F-genotype, P < 0.001). Increased expression of CD16 correlated with CD16-dependent degranulation of NK cells (R = 0.4; P = 0.02). Moreover, the V/V-genotype was significantly associated with a higher glomerulitis score and an independent risk factor (HR 1.98; P = 0.04) for decreased allograft survival. Death-censored graft survival in c-aABMR cases at 3 years follow-up was 33% for the FCGR3A 158 V/V-genotype versus 62% for the F/F-genotype. In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased graft survival in cases with c-aABMR.

scholarly journals Parallels between antibody-mediated rejection and ischemic kidney injury with respect to B cell activation

2019 ◽  
Vol 7 (S3) ◽  
pp. S151-S151
Author(s):  
Stuart J. Knechtle ◽  
Jean Kwun
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Kidney Injury ◽  
B Cell Activation ◽  
Antibody Mediated Rejection

Sipuleucel-T product characterization across different disease states of prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 42-42 ◽  
Author(s):  
Nadeem A. Sheikh ◽  
Eric Jay Small ◽  
David I. Quinn ◽  
Celestia S. Higano ◽  
Daniel W. Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
B Cell ◽  
Disease Burden ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Disease State ◽  
Cellular Composition ◽  
B Cell Activation ◽  
Activation Markers ◽  
Disease States

42 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). In the Phase 3 mCRPC trials, antigen presenting cell (APC) activation in sipuleucel-T correlated with overall survival. Here product characteristics of sipuleucel-T were compared in patients (pts) from trials in the neoadjuvant (n=42), asymptomatic or minimally symptomatic mCRPC (n=341), and mCRPC (n=104) disease states. Methods: Sipuleucel-T comprises 3 treatments approximately 2 wks apart. Cellular composition and APC activation (CD54 upregulation) were evaluated in all courses of sipuleucel-T, and cumulative CD54 upregulation was calculated for each patient. In some studies, cytokines were assayed from culture supernatants and T cell and B cell activation markers were assessed by flow cytometry during manufacture. Results: Baseline demographics were generally representative of each disease state; neoadjuvant pts were younger with less disease burden; mCRPC pts had the highest disease burden and more frequent prior chemotherapy. While neoadjuvant pts had greater levels of T cells, the patterns of APC activation were similar among all trials, with increased CD54 upregulation at the second and third treatment. The trend for cumulative fold increase in CD54 upregulation was significantly greater in earlier disease pts (neoadjuvant: 35.5, asymptomatic or minimally symptomatic mCRPC: 28.7, mCRPC: 21.8; p<0.0001 (Joncheere-Terpstra test)). During manufacture of the product, lymphocyte activation markers and cytokines consistently showed enhanced expression during the second and third treatments in all disease states. The lymphocyte activation and cytokine profiles were similar between early and later disease state pts. Conclusions: While cellular composition varied with disease state, manufacture of sipuleucel-T activated APCs in both early and late disease states of prostate cancer, and generated similar T and B cell activation and cytokine production profiles consistent with immunological prime-boost. APC activation tended to be more robust in earlier disease states.

scholarly journals Interplay of Antibody and Cytokine Production Reveals CXCL13 as a Potential Novel Biomarker of Lethal SARS-CoV-2 Infection

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Alexander M. Horspool ◽  
Theodore Kieffer ◽  
Brynnan P. Russ ◽  
Megan A. DeJong ◽  
M. Allison Wolf ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Activation ◽  
Immunological Response ◽  
Blood Type ◽  
B Cell Activation ◽  
Necrosis Factor Alpha ◽  
Cytokine Analysis ◽  
Potential Marker ◽  
Antibody Levels ◽  
Global Population

ABSTRACT The SARS-CoV-2 pandemic is impacting the global population. This study was designed to assess the interplay of antibodies with the cytokine response in SARS-CoV-2 patients. We demonstrate that significant levels of anti-SARS-CoV-2 antibody to receptor binding domain (RBD), nucleocapsid, and spike S1 subunit of SARS-CoV-2 develop over the first 10 to 20 days of infection. The majority of patients produced antibodies against all three antigens (219/255 SARS-CoV-2+ patient specimens, 86%), suggesting a broad response to viral proteins. Antibody levels to SARS-CoV-2 antigens were different based on patient mortality, sex, blood type, and age. Analyses of these findings may help explain variation in immunity between these populations. To better understand the systemic immune response, we analyzed the levels of 20 cytokines by SARS-CoV-2 patients throughout infection. Cytokine analysis of SARS-CoV-2+ patients exhibited increases in proinflammatory markers (interleukin 6 [IL-6], IL-8, IL-18, and gamma interferon [IFN-γ]) and chemotactic markers (IP-10 and eotaxin) relative to healthy individuals. Patients who succumbed to infection produced decreased IL-2, IL-4, IL-12, RANTES, tumor necrosis factor alpha (TNF-α), GRO-α, and MIP-1α relative to patients who survived infection. We also observed that the chemokine CXCL13 was particularly elevated in patients who succumbed to infection. CXCL13 is involved in B cell activation, germinal center development, and antibody maturation, and we observed that CXCL13 levels in blood trended with anti-SARS-CoV-2 antibody levels. Furthermore, patients who succumbed to infection produced high CXCL13 and had a higher ratio of nucleocapsid to RBD antibodies. This study provides insights into SARS-CoV-2 immunity implicating the magnitude and specificity of response in relation to patient outcomes. IMPORTANCE The SARS-CoV-2 pandemic is continuing to impact the global population, and knowledge of the immune response to COVID-19 is still developing. This study assesses the interplay of different parts of the immune system during COVID-19 disease. We demonstrate that COVID-19 patients produce antibodies to three proteins of the COVID-19 virus (SARS-CoV-2) and identify many other immunological proteins that are involved during infection. The data suggest that one of these proteins (CXCL13) may be a novel biomarker for severe COVID-19 that can be readily measured in blood. This information combined with our broad-scale analysis of immune activity during COVID-19 provides new information on the immunological response throughout the course of disease and identifies a novel potential marker for assessing disease severity.

scholarly journals Long-Term Immunosuppression Management

2021 ◽  
pp. CJN.15040920
Author(s):  
David Wojciechowski ◽  
Alexander Wiseman
Keyword(s):  
Graft Survival ◽  
Kidney Function ◽  
Calcineurin Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Kidney Transplant Recipients ◽  
Major Barrier ◽  
Antibody Mediated Rejection ◽  
Maintenance Immunosuppression

The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5–8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor–based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.

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