The B Lymphocyte Stimulator (BLyS) family of ligands and receptors regulates humoral immunity by controlling B lymphocyte survival and differentiation. Herein, we review the ligands and receptors of this family, their biological functions, and the biochemical processes through which they operate. Pre-immune B lymphocytes rely on BLyS signaling for their survival, whereas antigen experienced B lymphocytes generally interact more avidly with a homologous cytokine, A Proliferation Inducing Ligand (APRIL). The molecular basis for signaling via the three BLyS family receptors reveals complex interplay with other B lymphocyte signaling systems, affording the integration of selective and homeostatic processes. As our understanding of this system advances, molecular targets for manipulating humoral immunity in both health and disease should be revealed.
Targeting recycling endocytic receptors with specific Abs provides a means for introducing a variety of tumor-associated Ags into human dendritic cells (DCs), culminating in their efficient presentation to T cells. We have generated a human mAb (B11) against the mannose receptor that is rapidly internalized by DCs through receptor-mediated endocytosis. By genetically linking the melanoma Ag, pmel17, to Ab B11, we obtained the fully human fusion protein, B11-pmel17. Treatment of DCs with B11-pmel17 resulted in the presentation of pmel17 in the context of HLA class I and class II molecules. Thus, potent pmel17-specific T cells were cytotoxic toward gp100+ HLA-matched melanoma targets, but not HLA-mismatched melanoma or gp100− nonmelanoma tumor lines. Importantly, competitive inhibition of lysis of an otherwise susceptible melanoma cell line by cold targets pulsed with known gp100 CD8 T cell epitopes as well as a dose-dependent proliferative response to Th epitopes demonstrates that DCs can process targeted Ag for activation of cytotoxic as well as helper arms of the immune response. Thus, the specific targeting of soluble exogenous tumor Ag to the DC mannose receptor directly contributes to the generation of multiple HLA-restricted Ag-specific T cell responses.
CD30 is a promising target for antibody-based immunotherapy of Hodgkin lym-phoma (HL) and anaplastic large cell lym-phoma. To overcome the limitations from currently available murine anti-CD30 monoclonal antibodies (mAbs), a new fully human anti-CD30 antibody was generated. Binding properties were evaluated by recombinant CD30 capture enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell-sorter (FACS) flow cytometry. Activity of this new mAb was assessed in vitro using growth inhibition and antibody-dependent cellular cy-totoxicity (ADCC) assays on several cell lines. In vivo activity was determined in a solid as well as in a disseminated xe-nografted model of HL in severe combined immunodeficiency (SCID) mice. The mAb 5F11 showed specific binding to CD30 (cluster A). The ADCC assays indicated dose-dependent lysis of L540 cells when 5F11 was combined with human effector cells. Upon cross-linking in vitro, 5F11 inhibited the growth of CD30-expressing cell lines. In vivo, treatment with 5F11 induced a marked growth delay or even a complete regression of established xenografted HL in SCID mice. In the disseminated HL model, a high proportion of 5F11-treated mice experienced long-term survival. The new human anti-CD30 monoclonal antibody 5F11 shows promise as a means of CD30-targeted immunotherapy of malignant lympho-mas. Based on these results, a clinical phase 1 study in patients with refractory CD30 lymphoma has been initiated.
Purpose: The oncofetal antigen, human chorionic gonadotropin  subunit (hCG), is expressed by a number of carcinomas and is a prognostic indicator in renal, colorectal, bladder, and pancreatic cancers. We describe the development of a novel antibody-based dendritic cell (DC)-targeted cancer vaccine capable of eliciting cellular immune responses directed against hCG.Experimental Design: The tumor-associated antigen hCG was coupled genetically to a human anti-DC antibody (B11). The resulting fusion protein (B11-hCG) was evaluated for its ability to promote tumor antigen-specific cellular immune responses in a human in vitro model. Monocytederived human DCs from normal donors were exposed to purified B11-hCG, activated with CD40 ligand, mixed with autologous lymphocytes, and tested for their ability to promote hCG-specific proliferative and cytotoxic T-lymphocyte responses.Results: B11-hCG was found to be a soluble, welldefined, and readily purified product that specifically recognized the human mannose receptor via the B11 antibody portion of the fusion protein. B11-hCG functionally promoted the uptake and processing of tumor antigen by DCs, which led to the generation of tumor-specific HLA class I and class II-restricted T-cell responses, including CTLs capable of killing human cancer cell lines expressing hCG.Conclusions: Although other hCG vaccines have been shown to be capable of eliciting antibody responses to hCG, this is the first time that cellular immune responses to hCG have been induced by a vaccine in a human system. This DC-targeted hCG vaccine holds promise for the management of a number of cancers and merits additional clinical development.
Lymphocyte homeostasis poses a multi-faceted biological puzzle, because steady pre-immune populations must be maintained at an acceptable steady state to yield effective protection, despite stringent selective events during their generation. In addition, activated, memory and both short-and long-term effectors must be governed by independent homeostatic mechanisms. Finally, advancing age is accompanied by substantial changes that impact the dynamics and behavior of these pools, leading to cumulative homeostatic perturbations and compensation. Our laboratory has focused on the overarching role of BLyS family ligands and receptors in these processes. These studies have led to a conceptual framework within which distinct homeostatic niches are specified by BLyS receptor signatures, which define the BLyS family ligands that can afford survival. The cues for establishing these receptor signatures, as well as the downstream survival mechanisms involved, are integrated with cell extrinsic inputs via cross talk among downstream mediators. A refined understanding of these relationships should yield insight into the selection and maintenance of B cell subsets, as well as an appreciation of how homeostatic mechanisms may contribute to immunosenescence.
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