The identification of permissible HLA class II mismatches can prevent DSA in mismatched transplantation. The HLA-DR phenotype of recipients contributes to DSA formation by presenting allo-HLA-derived ...peptides to T-helper cells, which induces the differentiation of B cells into plasma cells. Comparing the binding affinity of self and nonself allo-HLA-derived peptides for recipients’ HLA class II antigens may distinguish immunogenic HLA mismatches from nonimmunogenic ones. The binding affinities of allo-HLA-derived peptides to recipients’ HLA-DR and HLA-DQ antigens were predicted using the NetMHCIIpan 3.1 server. HLA class II mismatches were classified based on whether they induced DSA and whether self or nonself peptide was predicted to bind with highest affinity to recipients’ HLA-DR and HLA-DQ. Other mismatch characteristics (eplet, hydrophobic, electrostatic, and amino acid mismatch scores and PIRCHE-II) were evaluated. A significant association occurred between DSA formation and the predicted HLA-DR presentation of nonself peptides (P=0.0169; accuracy = 80%; sensitivity = 88%; specificity = 63%). In contrast, mismatch characteristics did not differ significantly between mismatches that induced DSA and the ones that did not, except for PIRCHE-II (P=0.0094). This methodology predicts DSA formation based on HLA mismatches and recipients’ HLA-DR phenotype and may identify permissible HLA mismatches to help optimize HLA matching and guide donor selection.
Machine learning (ML) has shown its potential to improve patient care over the last decade. In organ transplantation, delayed graft function (DGF) remains a major concern in deceased donor kidney ...transplantation (DDKT). To this end, we harnessed ML to build personalized prognostic models to predict DGF. Registry data were obtained on adult DDKT recipients for model development (n = 55,044) and validation (n = 6176). Incidence rates of DGF were 25.1% and 26.3% for the development and validation sets, respectively. Twenty-six predictors were identified via recursive feature elimination with random forest. Five widely-used ML algorithms-logistic regression (LR), elastic net, random forest, artificial neural network (ANN), and extreme gradient boosting (XGB) were trained and compared with a baseline LR model fitted with previously identified risk factors. The new ML models, particularly ANN with the area under the receiver operating characteristic curve (ROC-AUC) of 0.732 and XGB with ROC-AUC of 0.735, exhibited superior performance to the baseline model (ROC-AUC = 0.705). This study demonstrates the use of ML as a viable strategy to enable personalized risk quantification for medical applications. If successfully implemented, our models may aid in both risk quantification for DGF prevention clinical trials and personalized clinical decision making.
The development of human leukocyte antigen (HLA) donor‐specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal ...protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy‐proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS‐free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA‐DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.
Luminex single antigen bead (SAB) assay utilizes beadsets coated with a set of cloned and purified HLA molecules, for monitoring serum anti-HLA antibodies. Particularly, the level of serum IgG ...against native HLA-I trimers (heavy chain (HC) and β2-microglobulin (β2m) with a peptide), expressed in allograft tissues is correlated with graft failure. In addition to native trimeric HLAI, the beadsets may carry HC only or the dimeric variants, peptide-free HC with β2m and β2m–free HC with or without peptides. Currently, three different HLA-I coated beadsets have been produced commercially. The HLA antigen density on one beadset was reported to be approximately 50% of that present on another beadset as evidenced by the binding of an anti-HLA-I mAb W6/32. To date, no efforts have been made to compare the relative distribution of HLA-I variants in these three beadsets. In this study, using monoclonal antibodies (W6/32, HC-10 and TFL-006) that can distinguish the structural variants based on their epitope specificities, the nature of the variants in the three beadsets were comparatively evaluated. One beadset (Beadset A, see Materials and methods for Brand and Manufacturer's names) (W6/32+/HC-10+/TFL-006+) carried at least three variants, while beadset B (W6/32+/HC-10+/TFL-006-) carried two (peptide-associated and peptide-free β2m–HC) and the beadset C (W6/32+/HC-10−/TFL-006-) carried exclusively the HLA-I trimer suggesting its usefulness for specific monitoring native HLA-I trimer antibodies. Because of the salient differences in the variants coated on the different beadsets, it would be warranted to investigate, if these differences are clinically relevant for monitoring serum anti-HLA antibodies in sensitized patients waiting for donor organs and in allograft recipients (274).
•Luminex HLA-I beads may carry several HLA-variants in addition to native trimeric HLAI.•Epitope specific monoclonal antibodies distinguished the variants on diverse beadsets.•Beadset A and Beadset B had three and two structural HLA-variants, respectively.•Beadset C had only the native trimeric HLA-I and specifically detect anti-HLA-I trimer.
Silver nanowires (AgNWs) hold great promise for applications in wearable electronics, flexible solar cells, chemical and biological sensors, photonic/plasmonic circuits, and scanning probe microscopy ...(SPM) due to their unique plasmonic, mechanical, and electronic properties. However, the lifetime, reliability, and operating conditions of AgNW-based devices are significantly restricted by their poor chemical stability, limiting their commercial potentials. Therefore, it is crucial to create a reliable oxidation barrier on AgNWs that provides long-term chemical stability to various optical, electrical, and mechanical devices while maintaining their high performance. Here we report a room-temperature solution-phase approach to grow an ultra-thin, epitaxial gold coating on AgNWs to effectively shield the Ag surface from environmental oxidation. The Ag@Au core-shell nanowires (Ag@Au NWs) remain stable in air for over six months, under elevated temperature and humidity (80 °C and 100% humidity) for twelve weeks, in physiological buffer solutions for three weeks, and can survive overnight treatment of an oxidative solution (2% H
2
O
2
). The Ag@Au core-shell NWs demonstrated comparable performance as pristine AgNWs in various electronic, optical, and mechanical devices, such as transparent mesh electrodes, surface-enhanced Raman spectroscopy (SERS) substrates, plasmonic waveguides, plasmonic nanofocusing probes, and high-aspect-ratio, high-resolution atomic force microscopy (AFM) probes. These Au@Ag core-shell NWs offer a universal solution towards chemically-stable AgNW-based devices without compromising material property or device performance.
Sensitization to human leukocyte antigens (HLA) in organ transplant patients causes graft rejection, according to the humoral theory of transplantation. Sensitization is almost ubiquitous as anti-HLA ...antibodies are found in almost all sera of transplant recipients. Advances in testing assays and amino acid sequencing of HLA along with computer software contributed further to the understanding of antibody-antigen reactivity. It is commonly understood that antibodies bind to HLA antigens. With current knowledge of epitopes, it is more accurate to describe that antibodies bind to their target epitopes on the surface of HLA molecular chains. Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross-reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes. Since 2006, we defined and reported 194 HLA class I unique epitopes, including 56 cryptic epitopes on dissociated HLA class I heavy chains, 83 HLA class II epitopes, 60 epitopes on HLA-DRB1, 15 epitopes on HLA-DQB1, 3 epitopes on HLA-DQA1, 5 epitopes on HLA-DPB1, and 7 MICA epitopes. In this paper, we provide a summary of our findings.
Luminex multiplex immunoassays enable simultaneous monitoring of Abs against multiple Ags in autoimmune, inflammatory, and infectious diseases. The assays are used extensively to monitor anti-HLA Abs ...in transplant patients for donor organ selection, desensitization, and assessing the risk for graft rejection. To monitor IgG Abs, fluoresceinated IgG constant H chain-binding polyclonal F(ab')
(
) is used as the fluoresceinated secondary Ab (2nd-Ab), whereas IgG subclasses are monitored with Fc-specific monoclonal whole IgG (
). The fluorescent signal from the 2nd-Ab is measured as mean florescence intensity (MFI). When
is used, the signal is amplified as a result of the binding of multiple polyclonal Fabs to the C region of primary IgH. The reliability of such amplification for Ab measurements was not validated, nor were MFIs compared with 1:1 binding of
to primary Abs. Comparing the MFIs of anti-HLA Abs obtained with
and
against normal human sera, IVIg, and allograft recipients' sera, it was observed that the number of HLA-Abs was notably higher with
than with
The MFIs of anti-HLA Abs also remained higher with
in the normal sera and in IVIg, but the reverse was true when the autologous and allogeneic IgG concentrations were augmented in allograft recipients. Indeed, MFIs of the de novo allo-HLA Abs were markedly higher with
than with
Serum titration established the superiority of
for monitoring MFIs of de novo allo-HLA Abs in allograft recipients. Avoiding false amplifications of the number and MFIs of anti-HLA IgG with
may minimize immunosuppressive therapies, maximize the number of donors for patients waiting for allografts, and enable better prediction of graft rejection.
Smart contact lenses have emerged as novel wearable devices. Due to their multifunctional biosensing capabilities and highly integrated performance, they provide a great platform for the diagnosis of ...eye diseases and the delivery of drugs. Herein, a brief history of the development of contact lenses is given. Then, the state‐of‐the‐art design and fabrication of smart contact lenses for biomedical applications, including contact lens materials, fabrication technologies, and integration, are presented. Furthermore, biosensors implemented in contact lenses to measure lactic acid, glucose, intraocular pressure, and other key metabolites in tears are highlighted. Applications of smart contact lenses in drug delivery are also described. These unique features make smart contact lenses promising diagnostic and treatment devices. Challenges and future opportunities for further applications of smart contact lenses in biomedicine are also discussed.
The state‐of‐the‐art design and fabrication of smart contact lenses for biomedical applications, including various contact lens materials, fabrication technologies, and electrical components, are presented. Also, challenges and future directions geared toward the development of highly functional smart contact lenses in health monitoring and drug delivery are discussed.
Aerogel‐based biomaterials are increasingly being considered for biomedical applications due to their unique properties such as high porosity, hierarchical porous network, and large specific pore ...surface area. Depending on the pore size of the aerogel, biological effects such as cell adhesion, fluid absorption, oxygen permeability, and metabolite exchange can be altered. Based on the diverse potential of aerogels in biomedical applications, this paper provides a comprehensive review of fabrication processes including sol‐gel, aging, drying, and self‐assembly along with the materials that can be used to form aerogels. In addition to the technology utilizing aerogel itself, it also provides insight into the applicability of aerogel based on additive manufacturing technology. To this end, how microfluidic‐based technologies and 3D printing can be combined with aerogel‐based materials for biomedical applications is discussed. Furthermore, previously reported examples of aerogels for regenerative medicine and biomedical applications are thoroughly reviewed. A wide range of applications with aerogels including wound healing, drug delivery, tissue engineering, and diagnostics are demonstrated. Finally, the prospects for aerogel‐based biomedical applications are presented. The understanding of the fabrication, modification, and applicability of aerogels through this study is expected to shed light on the biomedical utilization of aerogels.
Aerogel‐based biomaterials are increasingly being considered for biomedical applications due to their unique properties such as high porosity, hierarchical porous network, and large specific pore surface area. Based on the diverse potential of aerogels, this paper provides a comprehensive review of fabrication processes, materials, and additive manufacturing along with the biomedical application utilizing aerogel technology.
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