A Single Dose of Rituximab Does Not Deplete B Cells in Secondary Lymphoid Organs but Alters Phenotype and Function

Kamburova, Elena G.; Koenen, Hans J. P. M.; Borgman, Kyra J. E.; Berge, Ineke J. ten; Joosten, Irma; Hilbrands, Luuk B.

doi:10.1111/ajt.12220

Cited by 169 publications

(121 citation statements)

References 40 publications

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“…[29][30][31][32][33] However, several studies have shown that rituximab therapy effectively eliminates B cells from the peripheral blood but fails to effectively deplete all B cells within secondary lymphoid tissues. [34][35][36][37][38][39] Thus, whether PCs remaining in this setting are long-lived or dependent on replenishment by the residual B cells is unknown.…”

Section: Discussionmentioning

confidence: 99%

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Bhoj

Arhontoulis

Wertheim

et al. 2016

Blood

221

160

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• CD19-targeted T-cell immunotherapy reveals that a population of PCs lacking CD19 expression survives long-term, independent of B cells.• Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CTL019 immunotherapy.The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of longlived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent longterm survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19 1 CD20 1 B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity. (Blood. 2016;128(3):360-370)

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Section: Discussionmentioning

confidence: 99%

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Bhoj

Arhontoulis

Wertheim

et al. 2016

Blood

221

160

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“…After in vivo treatment with one dose of rituximab, we found that a B cell population remains in secondary lymphoid organs, despite complete depletion in peripheral blood (20). These remaining B cells mainly consist of switched memory (IgD-CD27þ) B cells, and have different functional capacities as compared to B cells obtained from lymph nodes of patients not treated with rituximab.…”

Section: Rituximab In Renal Transplantationmentioning

confidence: 93%

“…Indeed, an increase in circulating memory B cells has been associated with acute rejection in pediatric renal transplant recipients (17), while heart transplant recipients with higher percentages of na€ ıve B cells had a lower risk of acute rejection (18). However, we and others have previously shown that memory B cells are more resistant to depletion by rituximab than na€ ıve B cells (19,20).…”

Section: Rituximab In Renal Transplantationmentioning

confidence: 93%

Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety

Hoogen

Kamburova

Baas

et al. 2015

American Journal of Transplantation

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105

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We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double‐blind, placebo‐controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m2) or placebo during transplant surgery. Patients were stratified according to panel‐reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab‐treated (23/138, 16.7%) and placebo‐treated patients (30/142, 21.2%, p = 0.25). Immunologically high‐risk patients (PRA >6% or re‐transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab‐treated immunologically high‐risk patients, and rituximab‐ or placebo‐treated immunologically low‐risk (PRA ≤ 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p = 0.004). Neutropenia (<1.5 × 109/L) occurred more frequently in rituximab‐treated patients (24.3% vs. 2.2%, p < 0.001). After 24 months, the cumulative incidence of infections and malignancies was comparable. A single dose of rituximab as induction therapy did not reduce the overall incidence of BPAR, but might be beneficial in immunologically high‐risk patients. Treatment with rituximab was safe.

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“…The effects of rituximab extend beyond B cell depletion and may involve altering the phenotype and function of the remaining B cell subsets (18), normalization of T cell abnormalities (19), and promoting expansion of the regulatory T cell population (20,21). The possibility of T cell involvement in FSGS was suggested by an earlier study on renal biopsy tissue, where IL-2 receptora mRNA transcripts were detected in 14 of 20 patients with FSGS (22).…”

Section: Introductionmentioning

confidence: 99%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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Background and objectives Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified.Design, setting, participants, & measurements Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m 2 ) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab.Results Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154 + CD4 + CD3 + subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%628.1% versus 78.9%616.4%; P=0.03). IFN-g + CD3 + and IL-2 + CD3 + were similarly decreased in responders compared with nonresponders (0.6%60.8% versus 7.5%66.1%; P=0.003 and 0.2%60.5% versus 4.0%64.7%; P,0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154 + CD4 + CD3 + , 74.8%617.2%; IFN-g + CD3 + , 7.1%67.7%; and IL-2 + CD3 + , 7.9%610.9%; P,0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154 + CD4 + CD3 + ,83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-g + CD3 + ,2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2 + CD3 + ,0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response.Conclusions We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

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A Single Dose of Rituximab Does Not Deplete B Cells in Secondary Lymphoid Organs but Alters Phenotype and Function

Cited by 169 publications

References 40 publications

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

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