Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) can be utilized either as vectors or as targets for therapy. Patients with metastatic melanoma received CD34-DC vaccine that contains Langerhans' cells and interstitial DCs. DCs were pulsed with MART1, tyrosinase, MAGE3, gp100 and Flu-MP peptides, and KLH. DCs induced an immune response to control antigens in 16/18 patients. An enhanced immune response to 1 or more melanoma antigens (MelAgs) was seen in these 16 patients. The two patients failing to respond experienced rapid tumour progression. Six out of seven patients with immunity to two or fewer MelAgs had progressive disease 10 weeks after study entry, in contrast to tumour progression in only 1/10 patients with immunity to > two MelAgs. Since tumour immunotherapy targets autologous antigens we can learn from systemic autoimmunity such as systemic lupus erythematosus (SLE). As opposed to normal monocytes, SLE monocytes induce proliferation of allogeneic CD4+ T cells. SLE sera induce monocyte differentiation towards DCs in an IFNalpha-dependent mechanism. Spiking autologous serum with IFNalpha reproduces DC differentiation. 50% of SLE patients have high serum levels of IFNalpha, which could explain T/B lymphopenia. Yet, plasmacytoid DCs, a major IFNalpha source, are 80% decreased. pDCs and IFNalpha may play a role in SLE pathogenesis and therapy.
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PMID:Dendritic cells: controllers of the immune system and a new promise for immunotherapy. 1460 22

It is commonly believed that T cells have difficulty reaching tumors located in the brain due to the presumed "immune privilege" of the central nervous system (CNS). Therefore, we studied the biodistribution and anti-tumor activity of adoptively transferred T cells specific for an endogenous tumor-associated antigen (TAA), gp100, expressed by tumors implanted in the brain. Mice with pre-established intracranial (i.c.) tumors underwent total body irradiation (TBI) to induce transient lymphopenia, followed by the adoptive transfer of gp100(25-33)-specific CD8+ T cells (Pmel-1). Pmel-1 cells were transduced to express the bioluminescent imaging (BLI) gene luciferase. Following adoptive transfer, recipient mice were vaccinated with hgp100(25-33) peptide-pulsed dendritic cells (hgp100(25-33)/DC) and systemic interleukin 2 (IL-2). This treatment regimen resulted in significant reduction in tumor size and extended survival. Imaging of T cell trafficking demonstrated early accumulation of transduced T cells in lymph nodes draining the hgp100(25-33)/DC vaccination sites, the spleen and the cervical lymph nodes draining the CNS tumor. Subsequently, transduced T cells accumulated in the bone marrow and brain tumor. BLI could also detect significant differences in the expansion of gp100-specific CD8+ T cells in the treatment group compared with mice that did not receive either DC vaccination or IL-2. These differences in BLI correlated with the differences seen both in survival and tumor infiltrating lymphocytes (TIL). These studies demonstrate that peripheral tolerance to endogenous TAA can be overcome to treat tumors in the brain and suggest a novel trafficking paradigm for the homing of tumor-specific T cells that target CNS tumors.
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PMID:Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain. 1825 32

Upon transfer into T cell-deficient hosts, naive CD8(+) T cells typically undergo lymphopenia-induced proliferation (LIP, also called homeostatic proliferation) and develop the phenotypic and functional characteristics of memory CD8(+) T cells. However, the capacity of T cells with self-peptide/MHC specificity to respond in this way has not been intensively studied. We examined pmel-1 TCR transgenic CD8(+) T cells that are specific for an epitope from gp100, a protein expressed by melanoma cells and normal melanocytes. Despite their self-specificity, naive pmel-1 cells were inefficient at LIP in typical lymphopenic hosts. In CD132 (common gamma-chain)-deficient hosts, pmel-1 CD8(+) T cells underwent extensive proliferation, but, surprisingly, the majority of these cells retained certain naive phenotypic traits (CD44(low), CD122(low)) rather than acquiring the expected central-memory phenotype. Following LIP, pmel-1 T cells acquired the capacity to control B16F10 tumor growth, but only in common gamma-chain-deficient host mice. Together, these data suggest that LIP does not always favor expansion of self-specific CD8 T cells and that sustained extensive lymphopenia is required for such cells to exhibit tumor control.
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PMID:Self-specific CD8+ T cells maintain a semi-naive state following lymphopenia-induced proliferation. 2039 39

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of T lymphocyte homeostasis. SOCS1-deficient mice accumulate CD8(+) T cells, which display a memory-like phenotype and proliferate strongly to IL-15. Socs1(-/-) mice develop inflammatory skin lesions, however, the underlying mechanisms are not well understood. In order to investigate the role of SOCS1 in regulating CD8(+) T cells potentially reactive to tissue antigens (Ags) of the skin, we generated Socs1(-/-) mice expressing MHC-I-restricted Pmel-1 transgenic TCR specific to the melanoma-derived gp100 Ag, which is also expressed by normal melanocytes. Socs1(-/-) Pmel-1 cells express increased levels of memory markers CD44, Ly6C, CD122, and CD62L, and show downregulation of TCR and upregulation of CD5, suggesting in vivo TCR stimulation. However, stimulation of Socs1(-/-)Pmel-1 cells with gp100-derived peptide induced only marginal proliferation in vitro despite eliciting strong effector functions, which was associated with elevated Blimp-1 induction. Following adoptive transfer to Rag1(-/-) mice, Socs1(-/-)Pmel-1 cells underwent lymphopenia-induced proliferation and caused severe skin pathology characterized by inflammatory lesions in ears, muzzle, extremities, and eyes. These findings underscore the importance of SOCS1 in regulating potentially skin-reactive cytotoxic T lymphocytes, which could get activated under conditions that promote Ag-nonspecific, cytokine-driven proliferation.
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PMID:SOCS1 prevents potentially skin-reactive cytotoxic T lymphocytes from gaining the ability to cause inflammatory lesions. 2344 60

Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8 T cells, ova-specific (OT-I) and gp100-specific Pmel-1 T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66 mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR Tg T cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.
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PMID:Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. 2691 38