In Vivo Depletion of Lymphotoxin-Alpha Expressing Lymphocytes Inhibits Xenogeneic Graft-versus-Host-Disease

Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-α is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-α monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT-α is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-α mAb, designated MLTA3698A, was generated that specifically binds to LT-α in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-α mAb specifically depleted activated LT-expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-α antibody in treating immune diseases such as GVHD and autoimmune diseases

Long Lamai community ICT4D E‐commerce system modelling: an agent oriented role‐based approach

This paper presents the post‐mortem report upon completion of the Long Lamai e‐commerce development project. Some weaknesses with regards to the current software modelling approach are identified and an alternative role‐based approach is proposed. We argue that the existing software modelling technique is not suitable for modelling, making it difficult to establish a good contract between stakeholders causing delays in the project delivery. The role‐based approach is able to explicitly highlight the responsibilities among stakeholders, while also forming the contract agreement among them leading towards sustainable ICT4D

AIRRscape heatmaps comparing anti-SARS-CoV-2 antibodies, bulk BCR repertoires of four COVID-19 patients, and a healthy control bulk BCR repertoire.

AIRRscape heatmaps comparing anti-SARS-CoV-2 antibodies, bulk BCR repertoires of four COVID-19 patients, and a healthy control bulk BCR repertoire.</p

Dengue convergent clonotypes to CF1 (Zanini et al. 2018).

An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are plasmablast sequences reported by Zanini et al. (2018) isolated from two Colombian patients (d13 and d20), blue tips are antibody sequences from the BCR repertoire of patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan patient BCR repertoires.</p

HIV-1 convergent clonotypes to antibodies from Setliff et al. (2018; Fig 4).

(A) Convergent clonotypes to mAb 02-o in the 1_4_13 bin. (B) Convergent clonotypes to mAb 02-s in the 1_4_14 bin. (C) Convergent clonotypes to mAb HK20 in the 1_3_15 bin. A 70% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies, and green shaded tips are antibody sequences from HIV-1 patient BCR repertoires.</p

Workflow of repertoire data retrieval and processing.

Workflow of repertoire data retrieval and processing.</p

AIRRscape interface showing antibodies and CDR3 amino acid topology of selected antibody bin.

Selected bin is highlighted in the red box of Fig 2B. SHM values in blue are calculated after an additional tblastn search of the NCBI nr/nt database.</p

Supplementary figures.

Fig A in S1 Data. SARS-CoV-2 convergent clonotypes to mAb C102 in the 3_4_11 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies from 12 different studies, dark gray tips are antibody sequences from a healthy donor BCR repertoire, and orange through brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. Fig B in S1 Data. SARS-CoV-2 convergent clonotypes to mAb C125 in the 1_3_16 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies from 7 different studies, dark gray tips are antibody sequences from a healthy donor BCR repertoire, and orange through brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. Fig C in S1 Data. SARS-CoV-2 convergent clonotypes to mAb BD-494 in the 3_6_11 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies from 15 different studies, dark gray tips are antibody sequences from a healthy donor BCR repertoire, and orange through brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. Fig D in S1 Data. AIRRscape heatmaps comparing anti-HIV-1 antibodies and bulk BCR repertoires of eight HIV-1 patients. Fig E in S1 Data. HIV-1 convergent clonotypes to mAb CAP351_6m_6041 (Setliff et al. 2018; Fig 3) in the 1_6_14 bin. A 70% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies, and green shaded tips are antibody sequences from HIV-1 patient BCR repertoires. Fig F in S1 Data. AIRRscape heatmaps comparing isolated dengue plasmablasts and bulk BCR repertoires of dengue patients from Colombian and Nicaraguan cohorts. Fig G in S1 Data. Dengue convergent clonotypes to CF6 (Zanini et al. 2018). An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are plasmablast sequences reported by Zanini et al. (2018) isolated from two Colombian patients (d13 and d20), blue tips are antibody sequences from the BCR repertoire of patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan patient BCR repertoires. Fig H in S1 Data. Dengue convergent clonotypes to CF7 (Zanini et al. 2018). An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are plasmablast sequences reported by Zanini et al. (2018) isolated from two Colombian patients (d13 and d20), blue tips are antibody sequences from the BCR repertoire of patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan patient BCR repertoires. Fig I in S1 Data. Dengue convergent clonotypes to Parameswaran et al. (2018) motif ARQIGNWFDP similar to CF1 (Zanini et al. 2018). An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are plasmablast sequences reported by Zanini et al. (2018) isolated from two Colombian patients (d13 and d20), blue tips are antibody sequences from the BCR repertoire of patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan patient BCR repertoires. Fig J in S1 Data. SARS-CoV-2, HIV-1, & dengue convergent clonotypes to anti-SARS-CoV-2 mAb C102 in the 3_4_11 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies from 12 different studies, dark gray tips are antibody sequences from a healthy donor BCR repertoire, and orange through brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. Green shaded tips are antibody sequences from HIV-1 patient BCR repertoires. Gold tips are antibody sequences from a cohort of Nicaraguan dengue patient BCR repertoires. Fig K in S1 Data. SARS-CoV-2, HIV-1, & dengue convergent clonotypes to anti-SARS-CoV-2 mAb BD-494 in the 3_6_11 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-COVID-19 antibodies from 15 different studies, dark gray tips are antibody sequences from a healthy donor BCR repertoire, and orange through brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. Green shaded tips are antibody sequences from HIV-1 patient BCR repertoires. Gold tips are antibody sequences from a cohort of Nicaraguan dengue patient BCR repertoires. Fig L in S1 Data. HIV-1 & dengue convergent clonotypes to anti-HIV mAb 02-o (Setliff et al. 2018; Fig 4) in the 1_4_13 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are published anti-HIV-1 antibodies, while green shaded tips are antibody sequences from HIV-1 patient BCR repertoires. Blue tips are antibody sequences from the BCR repertoire of dengue patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan dengue patient BCR repertoires. Fig M in S1 Data. SARS-CoV-2 & dengue convergent clonotypes to anti-dengue mAb CF6 (Zanini et al. 2018) in the 1_4_13 bin. An 80% identity threshold is used to calculate convergence. Tips are colored by dataset source. Purple tips are plasmablast sequences reported by Zanini et al. (2018) isolated from two Colombian dengue patients (d13 and d20), blue tips are antibody sequences from the BCR repertoire of dengue patient d13, and gold tips are antibody sequences from a cohort of Nicaraguan dengue patient BCR repertoires. Brown shaded tips are antibody sequences from COVID-19 patient BCR repertoires. (PDF)</p

Datasets used in AIRRscape.

Datasets in italics are collections of antibodies.</p