Soluble molecules in intravenous immunoglobulin

Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20

Soluble molecules in intravenous immunoglobulin: benefits and limitations Maryam Azimi, Asghar Aghamohammadi, Hans D Ochs & Nima Rezaei To cite this article: Maryam Azimi, Asghar Aghamohammadi, Hans D Ochs & Nima Rezaei (2015): Soluble molecules in intravenous immunoglobulin: benefits and limitations, Expert Review of Clinical Immunology, DOI: 10.1586/1744666X.2016.1111138 To link to this article: http://dx.doi.org/10.1586/1744666X.2016.1111138

Published online: 09 Dec 2015.

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Date: 26 December 2015, At: 09:05

EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2015 http://dx.doi.org/10.1586/1744666X.2016.1111138

EDITORIAL

Soluble molecules in intravenous immunoglobulin: benefits and limitations Maryam Azimia, Asghar Aghamohammadib, Hans D Ochsc and Nima Rezaeia,b,d

Downloaded by [2.190.155.104] at 09:05 26 December 2015

a Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; bResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran; c Department of Pediatrics, University of Washington and Seattle Children’s Hospital Research Institute, Seattle, WA, USA; dUniversal Scientific Education and Research Network (USERN), Tehran, Iran

ABSTRACT

ARTICLE HISTORY

Because of its predominance, the main immunomodulatory function of IVIg is carried out by the IgG molecules; while, based on multiple studies, the immunomodulatory role of other soluble molecules in commercial IVIg products is impossible to ignore. Although the existence of these molecules and their suppressive effects on the immune response may be considered a positive contribution to the treatment of autoimmune disorders, their presence, half-life, accumulation and immunosuppressive actions in immunocompromised patients should be monitored by physicians and manufacturing companies.

Received 30 June 2015 Revised 4 October 2015 Accepted 19 October 2015

Intravenous immunoglobulin (IVIg) therapy is known as an effective treatment for variety of primary immunodeficiency diseases, (PIDs), especially in those with predominant antibody deficiencies [1]; however, its usage is also extended to a number of other immunological disorders, such as secondary immunodeficiencies and autoimmune diseases. [2,3] IVIg is a transfusion product prepared from a plasma pool collected from up to 30,000 healthy donors.[4] Standard IVIg preparations contain at least 98% highly purified immunoglobulin G (IgG) antibodies consisting primarily of monomers. The distribution of the IgG subclasses is similar to that of normal plasma. IgM is present in trace amounts and IgA content differs from preparation to preparation, even from batch to batch.[5] In order to prevent Ig aggregate formation, stabilizing elements such as sugars (e.g. maltose, sucrose) or amino acids (i.e. glycine or proline) have to be added. . In addition to these added ingredients, soluble proteins such as cytokines, sCD4, sCD8, sHLA molecules, sFasL and others have been identified in commercial IVIg preparations.[6–8] CONTACT Nima Rezaei © 2015 Taylor & Francis

[email protected]

KEYWORDS

Intravenous immunoglobulin; efficacy; immunomodulatory; sCD; sCD8; sHLA molecules; sFasL

The main effectiveness of IVIg as replacement therapy for patients with PID is its IgG content consisting of high-affinity polyclonal antibodies. However, its immunomodulatory function may be partially explained by the presence of other soluble immunomodulatory molecules.[9,10] While the mechanisms of the immunomodulatory activity of these soluble proteins are not well understood, the presences of these soluble molecules may be essential for immunomodulatory action of IVIg in autoimmune diseases; that is, recent investigations show a substantial increase in the percentage of Tregs in blood samples following IVIg therapy.[11] This expansion maybe partly via induction of cyclooxygenase (COX)-2-dependent prostaglandin E2 in antigenpresenting cells (APCs).[12] On the other hand, recent studies demonstrate that, regardless of the brand or the product batch, all IVIg preparations studied were found to equally inhibit the production of IL-17A from Th17 cells in vitro.[13] These observations suggest that the anti-inflammatory effect of IVIg helps to restore immune tolerance in autoimmune and inflammatory conditions. As no single mechanism appears to be responsible for the immunomodulatory effects of IVIg, it is practical to monitor both positive therapeutic and potential adverse effects. Sugars such as sucrose and maltose used as stabilizing agents in some IVIg preparations, as well as amino acids such as glycine and proline have been shown to suppress in vitro lymphocyte proliferation in the

Children’s Medical Center Hospital, Dr Qarib St, Keshavarz Blvd, Tehran 14194, Iran


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presence of mitogens or anti-CD3, while the repurified IgG component of the immunoglobulin preparations did not inhibit lymphocyte responses to PHA.[14] HLA Class I (HLA-I) antigens are not only expressed on the surface of nucleated cells, but are also present in serum as soluble HLA-I (sHLA-I). HLA Class-II (HLA-II) antigens, expressed on APCs and on activated T cells, are also present in serum as soluble molecules (sHLA-II). [8,15] In vitro studies have shown that soluble HLA molecules may modulate immune cell function in three ways: sHLA-I molecules may bind their ligands and inhibit T-cell function by receptor blockade; (ii) sHLA-I and sHLA-II molecules can be phagocytosed by APCs, degraded to peptides, and presented to CD4+ T cells in the context of membrane HLA-II antigens, a process known as indirect presentation; and sHLA-I may induce Fas ligand (FasL) expression and secretion by activated CD8+ T cells resulting in apoptosis of these cells.[16–18] FasL is a type II membrane protein mainly expressed by activated T cells and neutrophils.[19,20] Binding of cell-associated FasL to its target “Fas” prompts cell death in Fas-bearing cells.[21] It has been previously shown that FasL is also detectable in human serum in soluble form (sFasL).[22] Immunosuppressive concentrations of sHLA, sFasL and TGF-β are present in substantial amounts in commercially available IVIg preparations.[8,14,23] Several groups have reported a significant increase in plasma concentration of sHLA-I and TGF-β1 and TGF-β2 following treatment with IVIg at low (0.4 g IgG/kg) or high (0.8–1 g/kg) doses.[23] The observation CD8 T cells and neutrophils obtained from IVIg-treated patients, and that CD8 T cells and neutrophils obtained from healthy controls, when co-cultured with IVIg in vitro, significantly upregulated TGF-β1 mRNA and intracytoplasmic TGF-β1 suggests that the immune modulatory effects of IVIg may in part be due to “contaminating” biologic active molecules. The fact that immune depletion of sHLA-1 and/or sFasL abolishes the in vitro effect has been interpreted to demonstrate that the ability of IVIg to upregulate TGF-β1 might be causatively related to the immunosuppressive effect of sHLA-I and sFasL on the activation of CD8 T cells and neutrophils. The presence of sHLA-I and sFasL has also been reported in transfusion products.[24] Patients receiving allogeneic blood transfusions have a higher recurrence rate of malignant tumors, decreased rates of allograft rejection and increased postoperative bacterial infections.[25,26] Thus, the immunosuppressive molecules observed in blood products may be beneficial, as in IVIg when used for treatment of autoimmune or systemic inflammatory disorders; while their potential suppressive effects in immune compromised patients has to be considered and should be further evaluated.

Soluble CD4 (sCD4) and soluble CD8 (sCD8) are other molecules that have been observed not only in plasma but also in IVIg.[6] The CD4 and CD8 glycoproteins are primarily expressed on the surface of T helper and cytotoxic T lymphocytes. They serve as the functional ligands for HLA-I and HLA-II on APCs. Both CD4+ and CD8+ lymphocytes play fundamental roles in facilitating Ag presentation by APCs leading to T-cell activation. The existence of sCD4 in IVIg may allow its binding to HLA-II competing with MHC class II-restricted autoreactive T lymphocytes, resulting in immune tolerance that would be beneficial for patients with immune-mediated disorders [10] but detrimental for immune-deficient patients. Further studies are needed to define these controversial issues. Measurable concentrations of sCD8 in IVIg are rarely observed and its role is unknown. Because of its quantitative predominance, IgG is considered to provide the bulk of the immune modulatory function of IVIg. However, considering the data summarized here, the role of “contaminating” molecules regularly found in IVIg preparations cannot be ignored. It is imperative to monitor their potential effects on autoimmune diseases and to study the immunosuppressive actions that may adversely affect antibody-deficient patients.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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