Interleukin-2 correction of defectivein vitro T-cell mitogenesis in patients with common varied immunodeficiency

Abstract

We studied the ability of phytohemagglutinin (PHA) and two anti-T-cell monoclonal antibodies, OKT3 and Pan T2, to induce interleukin-2 (IL2) production and proliferation in peripheral blood lymphocytes (PBL) from 14 patients with combined varied immunodeficiency (CVI). The median values of endogenous IL2 produced by mitogen-stimulated PBL was significantly lower in patients than controls irrespective of the mitogen used. The patients, taken as a group, had a significantly decreased in vitro PBL response to mitogen stimulation when compared to controls. With the addition of a highly purified human IL2 preparation, the proliferative response in the majority of patients was significantly improved with all mitogens. Three patient groups could be distinguished: Group A (3/14) had full restoration of proliferative response with the addition of IL2, Group B (5/14) had partial restoration, and Group C (6/14) had no significant response. The monoclonal antibody, Pan T2, recognized a T-cell proliferative defect in 5 of 14 patients which neither PHA nor OKT3 recognized. This was not significantly corrected by the addition of IL2. This T-cell proliferative defect correlated with the lack of B-cell proliferation and immunoglobulin production in response to B-cell mitogens in three-fourths of the patients assayed. These data show that CVI patients are a heterogeneous group but have in common a decreased in vitro production of IL2 resulting in a proliferative defect which is correctable at least in part, in vitro, in the majority by the addition of purified IL2.

Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells

“…In all subgroups of CVID (A, B and C), which correlate with clinical status and B cell defect in this disease, mean PPD-specific responses were significantly reduced from normal values, similar to our previous report [10]. That this occurs in all subgroups of CVID patients contrasts with the defect in responses to mitogens which we and others have previously reported in only about 30% of patients [5,21,22], suggesting that the problem with antigen-driven T cell responses is more fundamental to the pathogenesis of CVID.…”

“…A subgroup of CVID patients show very poor T cell proliferation on stimulation with mitogens or phorbol with ionomycin [3,4]. This is associated with depression of lL-2 production, and some workers claim that proliferation can be restored to near normal levels by the addition of recombinant IL-2 (rIL-2) [5]. The finding that mRNA for IL-2 is grossly reduced in phytohaemagglutinin (PHA)-stimulated T cells from CVID patients [6], whether or antigen unresponsiveness of T cells from CVID patients.…”

TLR9 Activation Is Defective in Common Variable Immune Deficiency

“…Over the past decades, a number of studies have investigated immune defects in CVID. Although T cell subsets are perturbed (61,62), T cell activation (9), proliferation (63), and cytokine production are subnormal (64,65), apoptosis is enhanced (12,66), and monocyte dendritic cell defects are present (13,14); the defining hallmark of the disease is hypogammaglobulinemia and the lack of functioning B cells. Based on this characteristic, investigators have used a number of in vitro B cell functional studies to stratify patients into those with nonfunctional B cells, poorly functioning B cells or more normally responsive B cells (67)(68)(69).…”

Cytokines with Possible Clinical Utility

“…Among those affected are patients with primary and acquired immunodeficiency diseases, including common variable immunodeficiency (CVI) [18] and the acquired immunodeficiency syndrome (AIDS) [19,20], bone marrow transplant recipients [21], and patients with severe burns and hemophilia [22] [23,24]. Defects in lectin-and mitogen-induced T-cell proliferation are frequently reversible in vitro by exogenous IL2.…”