Hepatitis C virus (HCV) is a major health problem. However, the mechanism of hepatocyte infection is largely unknown. We demonstrate that the dendritic cell (

This report demonstrates SOL IL-5Ralpha transcript and protein up-regulation in NP. Soluble IL-5Ralpha differentiates nasal polyps with or without concomitant asthma. As SOL IL-5Ralpha is strongly up-regulated for disease and has antagonistic properties in vitro, our studies shed new light on the mechanisms of specific immunomodulatory therapies, such as anti-IL-5.

SUMMARYThe innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-b1, a rat monoclonal antibody recognizing the mouse IL-2 receptor b-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-b1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-b1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-b1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-b1. However, these animals died within 3 weeks postgrafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-b1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-b1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.

Severe combined immunodeficient (SCID) mice accept human xenografts and can act as a model for human immune functions. Murine natural killer cells (NK), however, represent an important barrier for the reconstitution of SCID mice with human peripheral blood leukocytes (Hu‐PBL). We investigated the effect on Hu‐PBL survival of pretreatment with TM‐β1, a rat monoclonal antibody for the mouse IL‐2 receptor beta chain. TM‐β1 greatly improved the survival of Hu‐PBL. Human lymphocytes, predominantly T cells, survived in the peritoneum and infiltrated spleen and lungs already 1 week after engraftment and liver and thymus from 2 weeks on. Secondary humoral responses were evaluated with Hu‐PBL from a donor immune to hepatitis‐B surface Ag (HBsAg) and tetanus toxoid (TT). TM‐β1 pretreatment enhanced the recall Ig response to HBsAg and did not affect the baseline anti‐TT Ig production. In conclusion, TM‐β1 pretreatment of SCID mice significantly improves the survival and functionality of the Hu‐PBL graft.

Human mAbs (HumAbs) have therapeutic potential against infectious diseases and cancer. Heretofore, their production has been hampered by ethical constraints preventing the isolation of Ag-specific activated B cells by in vivo immunization. Alternatively, severe combined immune deficient (SCID) mice, transplanted i.p. with human (Hu)-PBLs, allow the in vivo stimulation of human Ab responses without the usual constraints. Unfortunately, human B cells only represent a minor fraction of the surviving graft, they are scattered all over the animal body, and thus are hard to isolate for subsequent immortalization procedures. To prevent this dispersion and to provide the human B cells with a niche for expansion and maturation, SCID mice were engrafted with Hu-PBL directly into the spleen. Simultaneously endogenous murine NK cell activity was depleted by treatment with an anti-mouse IL-2 receptor β-chain Ab. During engraftment, human B lymphocytes became activated, divided intensely, and differentiated into plasmacytoid cells. In vivo exposure to a recall Ag after cell transfer induced expansion of Ag-specific B cell clones. One week after inoculation, human B cells were abundant in the spleen and could easily be recovered for fusion with a heteromyeloma line. This resulted in the formation of stable hybridoma cell lines that secreted Ag-specific HumAbs. Thus transplantation of human lymphoid cells in the spleens of immune deficient mice represents a model for the study of human T cell-dependent B cell activation and proves to be an excellent tool for the successful production of HumAbs.