The Interleukin‐2 Receptor, its Physiology and a New Approach to a Selective Immunosuppressive Therapy by Anti‐Interleukin‐2 Receptor Monoclonal Antibodies

Abstract

In this report we have summarized our findings on the IL-2 receptor and our attempts to find an IL-2 receptor targeted immunosuppressive therapy. IL-2 receptors are detectable in two different forms: as monomeric, surface expressed, and as dimeric, presumably non-surface expressed molecules. The dimeric form seems to be non-covalently bound to an as yet undefined 110 KD molecule. The functions of the monomeric versus the dimeric form, as well as that of the noncovalently bound molecule, and their relationship to high and low affinity IL-2 receptors are not yet clear and remain to be elucidated. Upon antigenic or mitogenic stimulation, IL-2 receptors became expressed at the surface of T-lymphocytes. Receptor expression is accompanied by the capacity of the cells to proliferate in response to IL-2. Resting T-cells do not proliferate in response to IL-2. IL-2 dependent proliferation of cells without external stimulation is either due to the presence of a small number of IL-2 receptor bearing cells in the respective population or due to a small number of IL-2 receptors present on the surface of cells. IL-2 itself does not induce IL-2 receptor expression on resting cells but has been shown to up-regulate its own receptor once expressed. In contrast to resting lymphocytes, some leukemic cells and early embryonic thymocytes in the species tested constitutively express IL-2 receptors. The role of such constitutively expressed receptors is not yet clear. As demonstrated in mice, the requirement(s) for induction of IL-2 receptor expression for the helper/inducer subset (Lyt-2+) are different from those of the cytotoxic/suppressor subset (L3T4+). In contrast to Lyt-2+ cells, the accessory cell requirement for L3T4+ cells could not be replaced by cytokines. Whether Lyt-2+ cells require an additional, not yet defined receptor inducing factor (RIF) besides IL-2 in order to become IL-2 receptor positive and to consequently proliferate in response to IL-2, is a matter of controversy. There is evidence that interleukin-1 and some functionally related factors produced by leukemic cells enhance expression and/or function of the IL-2 receptors. IL-2 receptors of the high and low affinity type expressed upon antigenic stimulation are cleared from the cell surface. As demonstrated in this report, the vast majority of them, probably those of low affinity type, are released from the cells continuously. The mechanism of their release and the possible immunoregulatory role of circulating receptors found in the serum of animals is not yet clear.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibody-Based Immunotoxins for the Treatment of Cancer

“…It is not expressed on resting lymphocytes and stem cells but is efficiently induced after T-cell activation. IL-2Rs have been detected on cells at high levels in autoimmune disorders and on malignant cells in different hematopoietic malignancies [59]. LMB-2 was evaluated in a phase I study that was completed in 2011.…”

Suppression of cell-mediated and humoral immune responses by an interleukin-2-immunoglobulin fusion protein in mice.

“…A more specific approach to inhibit selective immune function became feasible with the application of monoclonal antibodies. Anti-CD3, anti-CD4, and anti-CD25 antibodies are highly effective and block T cell-mediated immune responses in vitro and in vivo (1)(2)(3)(4). Recently, genetically engineered immunoligands such as CTLA4-IgG or IL2-IgM were used successfully to modulate the immune response to xeno-, allo-, and autoantigens (5)(6)(7)(8).…”

Soluble interleukin-2 receptor serum levels after allogeneic bone marrow transplantation as a marker for GVHD

“…3,4 Once activated, T cells express the interleukin-2 receptor (IL-2R), consisting of at least three subunits (␣, ␤ and ␥ c ) on their membrane. 5,6 Current understanding of the receptor is presented by Minami and coworkers. 6 Interleukin-2 binds to the ␤-subunit and is subsequently internalized, the ␣-subunit is shed from the cell surface and can be detected in the serum as soluble interleukin-2 receptor (sIL-2R).…”

“…7,8 Increased levels of sIL-2R have been detected in patients with high immune activity such as autoimmune diseases, 9 allograft rejection, 10,11 and severe infection. 12 Therefore in these settings treatment with anti-IL-2 receptor monoclonal antibodies would be of clinical value 5 as animal models have shown. 13,14 The use of anti-IL-2 receptor monoclonal antibodies has also been reported in the context of aGVHD treatment in animal models 15,16 as well as humans.…”