Human Immunology, Год журнала: 2024, Номер 85(6), С. 111163 - 111163
Опубликована: Окт. 24, 2024
Язык: Английский
Clinical Immunology, Год журнала: 2024, Номер 264, С. 110240 - 110240
Опубликована: Май 9, 2024
Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use anti-C5 eculizumab type-2 anti-CD20 obinutuzumab in two patients early ABMR. Eculizumab (900 mg IV) led to complete inhibition terminal complement cascade (unremarkable AP50 CH50 activity) prompt stoppage complement-dependent injury (clearance intra-graft C4d C5b-9 deposition). Despite inhibition, (1000 determined full long-lasting peripheral B-cell depletion, significant reduction all DSA. Graft function improved, remaining stable up three years follow-up. No signs active rebound DSA were detected. Obinutuzumab depletion production not affected by blockage. Further studies are needed confirm potential benefit association inhibitors.
Язык: Английский
Процитировано
3
Transplantation, Год журнала: 2024, Номер unknown
Опубликована: Авг. 28, 2024
In kidney transplantation, ongoing alloimmune processes—commonly triggered by HLA incompatibilities—can trigger chronic transplant rejection, affecting the microcirculation and tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in dysfunction accelerated failure. Numerous experimental translational studies have delineated a complex interplay of different immune mechanisms driving with antibody-mediated rejection (AMR) being an extensively studied variant. microvascular inflammation, hallmark lesion AMR, natural killer (NK) cells emerged as pivotal effector cells. Their essential role is supported immunohistologic evidence, bulk spatial transcriptomics, functional genetics. Despite significant research efforts, substantial unmet need for approved therapies persists, many trials yielding negative outcomes. However, several promising are currently under investigation, including felzartamab, monoclonal antibody targeting surface molecule CD38, which highly expressed NK antibody-producing plasma exploratory phase 2 trial late this compound has demonstrated potential resolving molecular morphologic activity predominantly cell function. These findings inspire hope effective treatments emphasize necessity further focusing on rejection.
Язык: Английский
Процитировано
3
Kidney360, Год журнала: 2024, Номер 5(8), С. 1207 - 1225
Опубликована: Июль 12, 2024
Exposure to HLA alloantigens through pregnancy, blood products, and previous transplantations induce powerful immunologic responses that create an barrier successful transplantation. This is commonly detected screening for antibodies using Luminex beads coated with antigens at transplant evaluation. Currently accepted approaches desensitization include plasmapheresis/low-dose or high-dose intravenous Ig plus anti-CD20. However, these are often unsuccessful because of the inability remove high titer circulating limit rebound by long-lived anti-HLA antibody secreting plasma cells (PCs) memory B (B MEM ). especially significant patients a calculated panel reactive 99%–100%. Newer approaches, such as imlifidase (IgG endopeptidase), rapidly inactivate IgG molecules antibody-free zone cleaving into F(ab’2) Fc fragments, thus eliminating complement cell-mediated injury graft. represents important advancement in desensitization. efficacy limited pathogenic rebound, increasing potential antibody-mediated rejection. Controlling requires new strategies address issues depletion inhibition PC responses. will likely require combination agents effectively deplete prevent immune cell activation pathways responsible rebound. Here, anti–IL-6 receptor (tocilizumab) (clazakizumab) could offer long-term control donor-specific Agents aimed PCs (anti-CD38 anti–B-cell maturation antigen×CD3) benefit highly sensitized patients. Complement inhibitors novel inhibiting neonatal recycling be Administering alone advance our ability desensitize maintain durable suppression post-transplant. After many years options, advanced therapeutics improve access kidney transplantation
Язык: Английский
Процитировано
2
Transplantation Direct, Год журнала: 2024, Номер 10(8), С. e1685 - e1685
Опубликована: Июль 18, 2024
Presensitized patients with donor-specific antibodies (DSAs) are at increased risk of antibody-mediated rejection (AMR) kidney allografts.1 The long-term consequences AMR serious because currently available therapeutic options lack lasting effectiveness.2 Targeting plasma cells to counter antibody production may hold promise for treating AMR.3 Daratumumab is a fully humanized monoclonal directed against CD38, glycoprotein expressed high levels on and, in addition, natural killer cells, which suggested act as effector AMR.4,5 Several case reports its efficacy the treatment and without multiple myeloma.6-8 Timing such therapy significant concern serum creatinine alone cannot distinguish subclinical injury, innovative tools necessary more precise diagnostics. Here, we describe severe DSA rebound associated by histology molecular assessments effectively reversed 6-mo course daratumumab. CASE DESCRIPTION patient 55-y-old man who has undergone fourth transplantation November 2022. deceased brain death donor was 61-y-old well-preserved function (estimated glomerular filtration rate [eGFR]: 2.4 mL/s). Despite level sensitization (calculated panel-reactive 91%), there only single anti-HLA class II present (specificity: DQA1*01:02/DQB1*06:02; mean fluorescence intensity [MFI]: 4200). Both actual cytotoxic flow T B crossmatch were negative. A detailed description HLA typing all donors recipient given Table S1 (SDC,https://links.lww.com/TXD/A680). exchange immediately before surgery performed desensitization. intravenous dose alemtuzumab (30 mg) applied perioperatively induction (Figure 1A). Peritransplant desensitization included 5 exchanges every other day, along IVIG (2 g/kg total).9 For maintenance immunosuppression, tacrolimus (target trough 8–12 µg/L), mycophenolate mofetil (2000 mg), tapered prednisone administered. Infection prophylaxis consisted valganciclovir trimethoprim/sulfamethoxazole. Graft developed 1B).FIGURE 1.: Clinical case. A, Therapy during follow-up. B, Renal function. C, DSAs. DSA, antibody; eGFR, estimated rate; MFI, intensity.At postoperative day (POD) 9, Luminex-based antigen testing revealed substantial increase reactivity. Specifically, preformed anti-DQA1*01:02/DQB1*06:02 (16 000 MFI) noticed presence 3 different DSA-targeting DR antigens (DRB1*12:02, DRB5*01:01 DRB3*02:02, maximum MFI 4600; Figure 1C). Tacrolimus exceeded target range (18.4 µg/L). On POD 12, acute tubular necrosis microvascular inflammation (MVI) or capillary C4d staining graft biopsy 2A1). However, Molecular Microscope Diagnostic System (MMDx) assessment showed finding moderate early stage 2A2 A3). Serum time 210 µmol/L 12 µg/L. Donor-derived cell-free DNA (dd-cfDNA; Prospera) profound fractions increasing 3.21% (negative result defined <1%). Clearly, after transplantation, dd-cfDNA rule out peritransplant injuries. considering rebound, planned administration rituximab (1 g) top protocol. complicated allergic reaction, thus received steroid bolus. discharged home 165 (eGFR 0.66 Another 30 an ongoing allograft injury (7.97%) despite stable function.FIGURE 2.: Histologic (A1, B1, C1) MMDx results (A2, A3, B2, B3, C2, C3, D1, D2) index surveillance biopsies. Histopathologic examination first biopsy, active second (glomerulitis shown red circles), resolution g remaining mild ptc (shown circle) third biopsy. Biopsies assignments specific archetypal phenotypes, MMDx-based analysis, depicted (yellow triangles) PC plots (PC1 vs PC2) based reference set 5087 biopsies.10 Colored circles indicate locations 6 archetype centers: R1: no rejection; R2: TCMR1; R3: TCMR2; R4: early-stage AMR; R5: R6: late-stage R7, minor centers—R1: normal; AKI1; AKI2; CKD; CKD/AKI; Minor CKD. development scores between follow-up Rejection classifier scores. D2, Injury Dashed lines, particular Banff histologic lesions. AKI, injury; AMR, cg, transplant glomerulopathy; CKD, chronic disease; g, glomerulitis; i, interstitial inflammation; MMDx, System; PC, principal component; ptc, peritubular capillaritis; t, tubulitis; TCMR, cell–mediated rejection.At 90, considerable MVI [g2] capillaritis [ptc2]), suggesting morphologic activity 2B1). 2B2 B3). immunodominant DSAs DQA1*01:02/DQB1*06:02 remained consistently elevated (15 MFI). 10.5 µg/L, virology screening BK virus replication (23 copies/ mL); however, did not show features polyomavirus nephropathy stable. As consequence, transiently reduced 500 mg/d. Based DSAs, worsening histological positive dd-cfDNA, initiated rescue daratumumab 115 when load decreased. subcutaneously (1800 mg/dose) 11 times period mo. Initially, week 4 times, followed finally monthly 2 282, coinciding last dose. extent (g0, ptc1) below diagnostic criteria definite 2C1). analysis indicated complete rejection-related 2C2 C3). current 0.8 mL/s), test 1 y yielded negative (0.08%). There rehospitalizations infection complications, but month completion treatment, experience COVID-19 disease treated remdesivir. During declined, eventually reaching positivity thresholds, until measurement 421 changes accompanied decrease non-DSA antibodies. Detailed descriptions days 90 285 2A–D. DISCUSSION HLA-incompatible remain chance some if acceptable mismatch programs long waiting compatible realistic. Our suggests targeting CD38 points critical role methods have transplantation. across low DQ reactivity crossmatches surgery. desensitization, detected posttransplantation. In be option than conventional histology,11,12 particularly receive mitigates does definitely alter alloimmune response. been implemented US centers our center routine assessments. salvage mo persisted unchanged, confirmed both injury. prognosis considered poor mostly presentation rejection. total over limited mo, primarily mitigate risks limit costs. This approach successful it led elimination achieved doses, notably, normalization Current uneventful, evidence dd-cfDNA. conclusion, well tolerated demonstrated converting normalizing histology, microscope, Future systematic interventional trials needed establish safety this larger cohorts.
Язык: Английский
Процитировано
2
ONCOLOGIE, Год журнала: 2024, Номер 26(3), С. 433 - 444
Опубликована: Фев. 27, 2024
Abstract Objectives The therapeutic effect against triple-negative breast cancer (TNBC) varies among individuals. Finding signatures to predict immune efficacy is particularly urgent. Considering the connection between microenvironment and hypoxia, hypoxia-related could be more effective. Therefore, in this study, we aimed sought construct a hypoxia-immune-related prediction model for identify targets. Methods Immune hypoxia status TNBC were investigated using single-sample Gene Set Enrichment Analysis (ssGSEA) Uniform Manifold Approximation Projection (UMAP). least absolute shrinkage selection operator (LASSO) multivariate Cox regression analysis employed build prognostic based on differentially expressed genes. Cancer Genome Atlas (TCGA) cohort, real-time quantitative polymerase chain reaction (qRT-PCR), immunofluorescence staining utilized analyze expression differences. Tumor dysfunction exclusion indexes used indicate of immunotherapy. Results We identified 11 related immunity. Among these genes, C-X-C motif chemokine ligand (CXCL) 9, 10, up-regulated tissues compared normal tissues. Furthermore, CXCL9, 11, 13 found enhance Conclusions These findings suggest value estimating risk patients with TNBC, are potential targets overcome resistance TNBC.
Язык: Английский
Процитировано
1
Advanced Healthcare Materials, Год журнала: 2024, Номер unknown
Опубликована: Июнь 6, 2024
For patients suffering from organ failure due to injury or autoimmune disease, allogeneic transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, true "holy grail" transplant immunology operational tolerance, which recipient exhibits a sustained lack alloreactivity toward unencountered antigen presented by donor graft. This outcome resultant critical changes phenotype and genotype immune repertoire predicated activation specific signaling pathways responsive soluble mechanosensitive cues. Biomaterials have emerged as medium for interfacing reprogramming these endogenous tolerance precise, minimally invasive, spatiotemporally defined manners. By viewing seminal contemporary breakthroughs induction through lens biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, depot effect, graft coatings, delivery tolerogenic cells, biomimicry situ reprogramming-this review emphasizes stunning diversity approaches field spotlights exciting future directions research come.
Язык: Английский
Процитировано
1
Heliyon, Год журнала: 2024, Номер 10(19), С. e38488 - e38488
Опубликована: Сен. 26, 2024
Язык: Английский
Процитировано
1
Oncology and Therapy, Год журнала: 2024, Номер 12(3), С. 375 - 394
Опубликована: Июнь 15, 2024
In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary rejection and poor function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, bortezomib, have been used for DSA desensitization, the effectiveness of desensitization outcomes in some patients remain unsatisfactory. this review, we summarized recent research on prevalence underlying mechanism DSAs pathogenesis failure. We mainly focused strategies DSAs, especially novel methods that are being investigated preclinical stage those with promising after preliminary clinical application.
Язык: Английский
Процитировано
0
Journal of Biological Chemistry, Год журнала: 2024, Номер 300(9), С. 107652 - 107652
Опубликована: Авг. 8, 2024
HLA-DQ molecules drive unwanted alloimmune responses after solid-organ transplants and several autoimmune diseases, including Type1 Diabetes celiac disease. Biologics with HLA as part of the design are emerging therapeutic options for these allo- conditions. However, soluble α β chains class II do not dimerize efficiently without their transmembrane domains, which hinders production. In this study, we examined feasibility inter-chain disulfide engineering by introducing paired cysteines to juxtaposed positions in HLA-DQ7, encoded HLA-DQA1*05:01 HLA-DQB1*03:01 respectively. We identified three variant peptide-HLA-DQ7-Fc fusion proteins (DQ7Fc) increased expression production yield, namely Y19C-D6C (YCDC), A83C-E5C (ACEC), A84C-N33C (ACNC). The mutated residues were conserved across all had limited solvent exposure. Further characterizations YCDC showed that protein is peptide-dependent; inclusion a higher-affinity peptide correlated expression. high-affinity alone was insufficient stabilizing DQ7 complex engineered bond. Multiple DQ7Fc variants demonstrated expected binding characteristics commercial anti-DQ antibodies two immunoassays cell-based assay. Lastly, dose-dependent killing DQ7-specific B cell hybridomas flow cytometric, complement-dependent cytotoxicity These data support novel approach producing functional potentially other candidate agents.
Язык: Английский
Процитировано
0
Frontiers in Immunology, Год журнала: 2024, Номер 15
Опубликована: Дек. 17, 2024
Bronchiolitis obliterans (BO) is a disease characterized by airway obstruction and fibrosis that can occur in all age groups. syndrome (BOS) clinical manifestation of BO patients who have undergone lung transplantation or hematopoietic stem cell transplantation. Persistent inflammation small airways make the irreversible, eventually leading to failure. The pathogenesis not entirely clear, but immune disorders are commonly involved, with various cells playing complex roles different subtypes. Accordingly, US Food Drug Administration (FDA) has recently approved several new drugs alleviate chronic graft-versus-host (cGVHD) regulating function cells, some which efficacy specifically cGVHD-BOS. In this review, we will discuss BO/BOS, introduce latest targeting as main target. This study emphasizes dysfunction an important driving factor its pathophysiology. A better understanding role system enable development targeted immunotherapies effectively delay even reverse condition.
Язык: Английский
Процитировано
0