Immunoglobulins mouse models

In the case of immunoglobulin, microarray data indicated the opposite effect that the Fc-receptor is elevated in chronic MS but not in acute lesions. Using Fcy-receptor knockout mice, the disease was found to be absent. Inter-venous immrmoglobulin therapy in the EAE mouse model was reported (see Lock, 2002, Reference 29). In summary. Lock et al. were able to apply the results of microarray-based gene expression clustering of a human disease pathological state (acute vs. chronic MS) to successfully identify fherapeutic targets for an animal model (EAE) potentially applicable to the human condition. 

Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T et al (2010) Human intravenous immunoglobulin provides protection against Ap toxicity by multiple mechanisms in a mouse model of Alzheimer s disease. J Neuroinflammation 7 90... 

A mouse model of lymphoma was used in pre-clinical studies to validate the vaccination procedure using a tobacco-derived idiotype-specific single-chain variable region fragment of the immunoglobulin from the cancerous mouse B-cell lymphoma [236]. Non-vaccinated mice died within 3 weeks of tumor injection, while 80% of the vaccinated mice were protected from the cancer and survived. 

Another crucial development was the finding that the BALB/c (Potter, 1972, 1977a) and later that the NZB strains of mice (Warner, 1975) when injected with paraffin oil develop a disease like multiple myeloma and also often excrete Bence Jones proteins. This not only provided an experimental model, but also permitted detailed comparison of mouse Bence Jones proteins and immunoglobulins with their human counterparts, an indispensable prerequisite for the study of antibody specificity. Relatively enormous quantities (kilograms in some instances) of Bence Jones proteins were obtainable from the urine of patients plasmapheresis yielded substantial quantities of myeloma proteins. Large amounts of the corresponding mouse proteins were also obtainable proteins from such neoplasms were in almost all instances monoclonal and homogeneous. 

Figure 2. A. Intratumor accumulation of various Cr-tagged proteins in solid tumor-bearing mice o, neocarzinostatin (NCS) (12 kDa) , SMANCS (16 kDa, but known to bind to albumin) , ovomucoid (29 kDa) , bovine serum albumin (69kOa) , mouse serum albumin (68 kDa) , mouse immunoglobulin G (160 kDa). Radiolabeled proteins were injected i.v. at time zero. Values are based on radioactivity (cf. Fig. 2). The tumor model in both A and B was solid sarcoma S-180 in mice. (From ref. 26, with permission). B. Relationship of drug distribution and molecular size to plasma concentration, AUC (area under the concentration curve), renal clearance, and intratumor uptake as expressed by percentage of injected dose. Putative polymer drugs are 1-Tyr-HPMA-copolymers of various molecular sizes given i.v. at 1.8 xlO cpm. The tumor model was sarcoma S-180 in mice. (From ref. 28 with permission).

Fig. 12.1. Model of nascent immunoglobulin heavy chain polyribosomal complex in mouse myeloma cells (MFC 11) indicating several cotranslational modification events. (1) Cleavage of the amino terminal signal peptide (2) formation of intrachain disulfide bonds (3) formation of interchain disulfide bonds with light chain (indicated by the thick line) (4) transfer of core oligosaccharide (CHC) to asparaginyl acceptor (X). About half of the nascent heavy chains form an interchain disulfide bond with a complete light chain before heavy chain completion and release from the polysomal complex (from Bergmann and Kuehl, 1979c, courtesy of Kuehl).

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