Dataset Information

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

ABSTRACT: The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease.

Methods

We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort.

Results

Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D⁺ transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation.

Conclusions

Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.

SUBMITTER: Looney CM

PROVIDER: S-EPMC9851678 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

Looney Cary M CM Schroeder Aaron A Tavares Erica E Garg Jay J Schindler Thomas T Vincenti Flavio F Redfield Robert R RR Jordan Stanley C SC Busque Stephan S Woodle E Steve ES Khan Jared J Eastham Jeffrey J Micallef Sandrine S Austin Cary D CD Morimoto Alyssa A

Transplantation direct 20230119 2

The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease.<h4>Methods</h4>We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and ...[more]

PMID: 36700064

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Project description:A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR Vβ-repertoire. Here, we assessed the impact of ESRD on the TCR Vβ-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR Vβ-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR Vβ-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR Vβ-family. CD8+, but not CD4+, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8+ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR Vβ-family in particular and expansions were predominantly observed within the CD8+ T cell compartment. All ESRD patients had expanded TCR Vβ-families within total CD8+ T cells and the median (IQ range) number of expanded TCR Vβ-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR Vβ-families within naive CD8+ T cells as 8 out of 10 patients had expanded TCR Vβ-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8+ T cells. In conclusion, loss of renal function skews the TCR Vβ-repertoire already in younger patients by inducing expansions of different TCR Vβ-families within the various T cell subsets, primarily affecting the CD8+ T cell compartment. This skewed TCR Vβ-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

Dataset Information

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

Methods

Results

Conclusions

Publications

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

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