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Marrow Purging And Stem Cell Preparation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Denis C. Roy, Nadine Beauger, Martin Gyger
CD33 is a surface glycoprotein of 67 kd, member of the immunoglobulin superfamily, and homologous to sialoadhesin, myelin-associated glycoprotein and CD22 antigen, and a particularly appealing antigen to target AML cells (Simmons and Seed, 1988; Freeman et al., 1995; Griffin et al., 1984; Takahashi et al., 1992). Indeed, greater than 80% of AML cells express this sialic acid-dependent cell adhesion molecule (Freeman et al., 1995; Griffin et al., 1984; 1986). Moreover, it is found on the majority of leukemia progenitor cells (L-CFC) in almost all AML patients evaluated (95%) (Griffin and Lowenberg, 1986). MY9, a mAb with reactivity against CD33, in combination with C is capable of eliminating 3.6 logarithms (logs) of clonogenic HL-60 cells (Griffin et al., 1984; Roy et al., 1991). When its effect was measured against normal hematopoietic progenitors, MY9+C inhibited the growth of 99% of day 7 and 14 CFU-GM and 53% of CFU-GEMM (Roy et al., 1991; Griffin et al., 1984; Griffin and Lowenberg, 1986). Following purging, hematologic reconstitution would thus probably originate from CFU-GEMM progenitors, which were only partially eliminated by such treatment, and from the hematopoietic progenitor cells that do not express CD33 (Griffin, 1987). With these results, Robertson et al. used CD33+C to treat marrow grafts from 12 patients with AML in CR2 (10 pts), CR1 (1 pt) and CR3 (1 pt). Neutrophil engraftment* was achieved at a median interval of 43 days, and platelet engraftment* at 92 days following autologous PCT. The DFS at 3 to 4 years was estimated at 33% with 4 patients in continuous CR at 3 to 5 years post PCT. These results clearly demonstrate that it is possible to target AML clonogenic cells for purging, and that radical eradication of CFU-GM and even partial elimination of CFU-GEMM do not irreversibly impair engraftment.
The sialoglycan-Siglec glyco-immune checkpoint – a target for improving innate and adaptive anti-cancer immunity
Published in Expert Opinion on Therapeutic Targets, 2019
Although all Siglecs recognize sialoglycans, there are considerable differences in the binding preferences of these receptors. Early experiments determined whether Siglecs bind to Sia linked by α2,3 linkage (like Siglec-1/sialoadhesin and Siglec-4/MAG), α2,6 linkage (like Siglec-2/CD22) or both (like Siglec-5, −9 and −10) [39]. Newer methods like sialoglycan-microarrays have provided evidence that binding of Siglecs to sialoglycans is more complex and other parameters like acetylation, fucosylation, branching of the underlying glycan chain as well as additional residues on the sialic acid themselves can influence the binding [40–42]. However, different methods used in different experiment make it difficult to define a definite binding profile, but it shows that some Siglecs like Siglec-2 and Siglec-8 have a rather specific binding profile with only few binding structures [43], while others like Siglec-3, −9 and −10 show a rather broad binding spectrum [42,44]. In addition, structural similarity of Siglecs does not automatically implicate similar ligand binding. For example, Siglec-7 and Siglec-9 are structurally very similar but differ in their binding profile to sialoglycans [45]. While α2,6-linked Sia is recognized by both receptors, Siglec-7 recognizes α2,8-linked disialylated glycans and Siglec-9 binds a broad range of sialoglycans including α2,3-linked Sia and also recognizes sialoglycans with a fucose residue attached to the glycan chain [41,46]. Paired Siglec receptors, i.e. Siglec-5/-14 or Siglec-11/-16 have the same binding spectrum.
Targeting strategies of liposomal subunit vaccine delivery systems to improve vaccine efficacy
Published in Journal of Drug Targeting, 2019
Rui Yu, Yaping Mai, Yue Zhao, Yanhui Hou, Yanhua Liu, Jianhong Yang
A macrophage-restricted endocytic receptor, Sialoadhesin (Sn or CD169), which belongs to the sialic acid binding immunoglobulin-like lectins (siglec) family, is expressed on specific subsets of resident macrophages and inflammatory macrophages [22,23]. Therefore, antigens can be targeted to Sn/CD169-expressing macrophages by using anti-Sn/CD169 antibodies or high-affinity glycan ligands of Sialoadhesin. Several reports have used such approaches to elicit and improve antigen-specific immune responses. Weihsu et al. have constructed Sn/CD169 ligand decorated liposomal nanoparticles and have found that Sn-targeted liposomes are effectively taken up by bone marrow-derived macrophages and significantly promote the proliferation of antigen-specific T cells [23].
Campylobacter jejuni induces autoimmune peripheral neuropathy via Sialoadhesin and Interleukin-4 axes
Published in Gut Microbes, 2022
Ankit Malik, Jean M. Brudvig, Barbie J. Gadsden, Alexander D. Ethridge, Linda S. Mansfield
Sialoadhesin (Sn, Siglec-1 or CD169) is a type1 transmembrane protein and a member of the Sialic acid binding Ig-like lectin (Siglec) family. Siglec-1 is expressed by metallophilic macrophages and activated dendritic cells (DC) at the site of afferent lymphatics in the spleen and the lymph nodes, and at the base of the crypts in the colon, which are sites of frequent invasion by pathogens.21,22 Therefore, anatomical location of Siglec-1-expressing antigen presenting cells such as DCs and macrophages suggests their role as a sentinel for primary contact with pathogens, and apoptotic or cancer cells. Siglec-1 binds to N-acetylneuraminyl alpha 2-3-galactose (α-2-3 Nan-gal) containing glycolipids and glycoproteins, which facilitates uptake of HIV by activated DC and macrophages in vitro.23,24 Bax et al. have shown that lipooligosaccharide (LOS) of GBS isolates is α-2,3 sialylated, which facilitates binding to Siglec-1.16 Further, this α-2,3 sialylation of the LOS promotes Type 2 maturation in a human DC-T cell coculture system.25 A role for Siglec-1 in phagocytosis of C. jejuni and primary IFN induction after intra-peritoneal infection has also been demonstrated.26–28 Yet, the role of Siglec-1 in C. jejuni induced diseases has not been addressed. Further, it is well established that IL-10 is a principal anti-inflammatory mediator for many auto-inflammatory diseases including IBD and multiple sclerosis and the animal model experimental autoimmune encephalomyelitis (MS/EAE).29 It has also been shown that naive IL-10−/− mice have a higher number of T cells with autoreactive T cell receptors (TCR) in their lymphoid organs.30 Therefore, we hypothesized that C. jejuni-induced autoimmune response in vivo is mediated by IL-4 and Siglec-1 axes, and these responses are amplified in the absence of IL-10. Experiments were conducted in C57BL/6 and C57BL/6 IL-10−/− models to address this hypothesis.