Characterization of the T cell receptor repertoire causing collagen arthritis in mice

Collagen type II-induced arthritis (CIA) is generated in susceptible rodent strains by intradermal injections of homologous or heterologous native type II collagen in complete Freund's adjuvant. Symptoms of CIA are analogous to those of the human autoimmune disease, rheumatoid arthritis. CIA is a model system for T cell-mediated autoimmune disease. To study the T cell receptor (TCR) repertoire of bovine type II-specific T cells that may be involved in the pathogenesis of CIA in DBA/1Lac.J (H-2q) mice, 13 clonally distinct T cell hybridomas specific for bovine type II collagen have been established and the alpha and beta chains of their TCRs have been analyzed. These T cell hybridomas recognize epitopes that are shared by type II collagens from distinct species and not by type I collagens, and exhibit a highly restricted TCR-alpha/beta repertoire. The alpha chains of the TCRs employ three V alpha gene subfamilies (V alpha 11, V alpha 8, and V alpha 22) and four J alpha gene segments (J alpha 42, J alpha 24, J alpha 37, and J alpha 32). The V alpha 22 is a newly identified subfamily consisting of approximately four to six members, and exhibits a high degree of polymorphism among four mouse strains of distinct V alpha haplotypes. In addition, the beta chains of the TCRs employ three V beta gene subfamilies (V beta 8, V beta 1, and V beta 6), however the V beta 8.2 gene segment is preferentially utilized (58.3%). In contrast, the J beta gene segment usage is more heterogeneous. On the basis of the highly limited TCR-alpha/beta repertoire of the TCRs of the panel of bovine type II-specific T cell hybrid clones, a significant reduction (60%) of the incidence of arthritis in DBA/1Lac.J mice is accomplished by the use of anti-V beta 8.2 antibody therapy

Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells

Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8α+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-γ. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses

Epidermal {gamma}{delta} T cells sense precancerous cellular dysregulation and initiate immune responses

Hyperplasia associated with a loss of tissue homeostasis can induce DNA replication stress, leading to precancerous dysregulation. Epidermal {gamma}{delta} T cells reside in the primary barrier that protects against diverse environmental insults; however, the functions of these T cells in tissue surveillance are not completely understood. In mice with inducible Notch1 inactivation in keratinocytes that causes epidermal hyperplasia, epidermal {gamma}{delta} T cells sensed stressed keratinocytes and migrated into the cutaneous draining lymph nodes. Simultaneous induction of β-galactosidase (β-Gal) as a putative antigen expressed in the process of precancerous dysregulation and Notch1 ablation in the epidermis resulted in elevated β-Gal-specific IgG2a production. Epidermal {gamma}{delta} T cells were found to have the capacity to express chemokine (C-C motif) receptor 7 and migrate into the lymph nodes. Cutaneous draining lymph node cells in Notch1-inactivated mice expressed high levels of IFN-{gamma} upon anti-CD3 plus anti-CD28 stimulation. Furthermore, induced expression of β-Gal in mice that lacked epidermal {gamma}{delta} T cells failed to induce anti-β-Gal IgG. These results suggest that epidermal {gamma}{delta} T cells play an essential role in the initiation process of epidermal antigen-specific humoral immune responses and demonstrate the importance of epidermal {gamma}{delta} T cells in sensing precancerous dysregulation and activating adaptive immunity

Studies on the host immune response in cancer Part I. Effect on immunopotentiators on mouse foot pad reaction against syngeneic tumor cell

The immuno-modulating effect of three immunopotentiators (OK-432, PS-K, Levamisole) was studied in MH-134 bearing C3H/He mice using foot pad reaction. When tumor bearing mice were injected their own tumor cells in foot pad, foot pad thickning was observed. Microscopic examination revealed that this thickning was not due to tumor growth but caused by polymorphonuclear and mononuclear cell infiltrations. This reaction was specific to their own tumor cells and was able to be transfered by spleen cells and peritoneal exudate cells. Immunopotentiators, when administered prior to tumor inoculation, these three agents had no effects on foot pad reaction, but when administered after tumor inoculation PS-K enhanced the foot pad reaction. Although cyclophosphamide had a significant suppressive effects on foot pad reaction, the reaction was restored by the concomitant use of these three immunopotentiators. This findings suggested that these immunopotentiators might restore the patient's immunity against one's own tumor when used concomitantly with cytotoxic agents in the management of cancer patient. On the other hand, concomitant use of carragheenan with OK-432 or Levamisole resulted in enhancing the suppressive effect cauced by carragheenan alone

Studies on the host immune response in cancer Part I. Effect on immunopotentiators on mouse foot pad reaction against syngeneic tumor cell

The immuno-modulating effect of three immunopotentiators (OK-432, PS-K, Levamisole) was studied in MH-134 bearing C3H/He mice using foot pad reaction. When tumor bearing mice were injected their own tumor cells in foot pad, foot pad thickning was observed. Microscopic examination revealed that this thickning was not due to tumor growth but caused by polymorphonuclear and mononuclear cell infiltrations. This reaction was specific to their own tumor cells and was able to be transfered by spleen cells and peritoneal exudate cells. Immunopotentiators, when administered prior to tumor inoculation, these three agents had no effects on foot pad reaction, but when administered after tumor inoculation PS-K enhanced the foot pad reaction. Although cyclophosphamide had a significant suppressive effects on foot pad reaction, the reaction was restored by the concomitant use of these three immunopotentiators. This findings suggested that these immunopotentiators might restore the patient's immunity against one's own tumor when used concomitantly with cytotoxic agents in the management of cancer patient. On the other hand, concomitant use of carragheenan with OK-432 or Levamisole resulted in enhancing the suppressive effect cauced by carragheenan alone

Studies on the host immune response in cancer Part Ⅱ. Host immune response in lung cancer patients during chemotheraphy

Fifty patients with nonresectable lung cancer were treated with a combination of cyclophosphamide, vincristine, methotrexate and procarbazine (COMP). Twentyfour patients (50%) of 48 evaluable patients responded to the therapy. Immune function, including total lymphocyte counts, T and B lymphocyte counts, in vitro lymphocyte blastogenesis by PHA and PPD and PHA skin reaction, were evealuated serially in reference to intensive cancer chemotherapy. The results obtained were as follows: 1) Although total lymphocyte counts, T and B lymphocytes counts, and in vitro blastgenic activity by PHA were significantly decreased immediately after COMP therapy, these parameters recovered to pretreatment level approximately within 3 to 4 weeks interval to next COMP therapy, there were no significant changes in PPD and PHA skin reaction following COMP therapy. 2) There was no relationship between pretreatment immune function and response to COMP therapy. 3) Recovery from impaired immune function was noted occasionally among the responders to COMP therapy. 4) A close relationship was noted between pretherapy response to PHA skin reaction, as well as pretherapy performance status, and survival of stage Ⅲ lung cancer patients treated with COMP therapy