Strong increase in the percentage of the CD8_bright+CD28_‐ T‐cells and delayed engraftment associated with cyclosporine‐induced autologous GVHD

Abstract

Four children with acute lymphoblastic leukaemia had autologous bone marrow (BM) or peripheral stem cell (PSC) transplantation with low dose of cyclosporine (CsA, 1 mg/kg/d i.v. during the first 28 d) to induce an autologous GVHD (auto‐GVHD). Two children did not have clinical auto‐GVHD and they relapsed 3 and 4 months after treatment. The 2 other children had clinical signs of auto‐GVHD (grade I and grade II): they both are in complete remission but after a first normal haematological recovery they had a prolonged period of aplasia until month 9 for 1 patient and still persistent at month 7 in the other case. We studied lymphocyte subsets reconstitution after transplantation in these patients. All patients had an important decrease in the CD4/CD8 ratio related both to a strong decrease in the CD4+ cells and a strong increase in the CD8+ cells. Most of the CD8+ cells were of the CD8bright+CD28‐ phenotype. These CD8bright+CD28‐ T‐cells represented from 33% to 68% of the total lymphocytes. We discuss the role of these cells after autologous transplantation with CsA, and wonder if these cells could mediate cytotoxicity. In conclusion, among 4 children who received autologous BM or PBC transplantation with low dose of CsA, we observed a complete remission after an auto‐GVHD and a prolonged period of aplasia in 2 patients and a relapse of leukaemia in 2 other patients. All these 4 patients had an increase in the CD8bright+CD28‐ T lymphocytes.

Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models

“…ICOS appears particularly important for the function of several activated and/or effector T cell subsets, including differentiated types 1, 2, and 17, as well as follicular helper T cells (TFH) [ 12 ]. Indeed, activated T cells often downregulate CD28 and/or become less dependent on CD28 costimulation, and CD28-negative T cells accumulate in various inflammatory diseases, correlating with disease activity and lack of responsiveness to abatacept [ 13 – 19 ]. In contrast, ICOS upregulation correlates with disease activity in several inflammatory diseases [ 20 – 24 ], and in preliminary studies, the anti-ICOSL mAb prezalumab (AMG-557) demonstrated some beneficial activity on the arthritis of systemic lupus erythematosus (SLE) (NCT04058028 [ 25 ];), as well as on overall disease activity in Sjögren’s syndrome (SjS) (NCT02334306).…”

First‐in‐human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist, in healthy adult subjects

“…[5][6][7][8][9] Indeed, CD28-negative T cells accumulate in various inflammatory diseases, correlating with disease activity and lack of responsiveness to abatacept. [10][11][12][13][14][15][16] ICOS is the most closely related immunoglobulin superfamily member to CD28. Unlike CD28, it is not expressed in naïve T cells but rapidly upregulates after activation and may represent a key pathogenic pathway unaddressed by CD28 pathway antagonism.…”

“… 5 , 6 , 7 , 8 , 9 Indeed, CD28‐negative T cells accumulate in various inflammatory diseases, correlating with disease activity and lack of responsiveness to abatacept. 10 , 11 , 12 , 13 , 14 , 15 , 16 …”

“…However, abatacept and/or other inhibitors of the CD28 pathway alone have been unsuccessful in clinical trials for several other inflammatory diseases including inflammatory bowel disease, systemic lupus erythematosus and lupus nephritis, and multiple sclerosis, suggesting that an additional costimulatory pathway(s) compensates in the presence of CD28/CD80 or CD86 blockade (5)(6)(7)(8)(9). Indeed, CD28-negative T cells accumulate in various inflammatory diseases, correlating with disease activity and lack of responsiveness to abatacept (10)(11)(12)(13)(14)(15)(16).…”

ALPN-101 (Acazicolcept) a Dual ICOS/CD28 Antagonist, Demonstrates Efficacy in Systemic Sclerosis Preclinical Mouse Models

“…ICOS appears particularly important for the function of several activated and/or effector T cell subsets, including differentiated types 1, 2, and 17, as well as follicular helper T cells (TFH) (12). Indeed, activated T cells often downregulate CD28 and/or become less dependent on CD28 costimulation, and CD28-negative T cells accumulate in various in ammatory diseases, correlating with disease activity and lack of responsiveness to abatacept (13)(14)(15)(16)(17)(18)(19). In contrast, ICOS upregulation correlates with disease activity in several in ammatory diseases (20)(21)(22)(23)(24), and in preliminary studies, the anti-ICOSL mAb prezalumab (AMG-557) demonstrated some bene cial activity on the arthritis of systemic lupus erythematosus (NCT04058028 ; (25)), as well as on overall disease activity in Sjögren's syndrome (NCT02334306).…”