The list of organ-specific autoimmune diseases (AID) is expanding. This is particularly true for T-cell-mediated AID, the pathophysiology of which has largely been ignored until recently. The best arguments for T-cell involvement in AID, although indirect, are the presence of a local T-cell infiltrate and the dramatic sensitivity of the disease to T-cell-selective immunosuppressive agents (e.g. cyclosporin A) as in the case of insulin-dependent (type I) diabetes mellitus (IDDM) and psoriasis. This paper will review current questions concerning the etiology and pathogenesis of organ-specific AID.
The ovine and caprine lentiviruses infect monocytes, and the viral DNA is integrated into the cellular DNA. The provirus remains silent until the monocyte matures into a macrophage. Intrinsic to this maturation is the induction of a class of immediate early genes in the monocyte that includes the transcription factors JUN and FOS. These transcription factors are thought to couple short-term signals in the cell to long-term cellular differentiation by regulation of specific cellular genes. Thus, JUN and FOS bind to the AP-1 site in the promoters of cellular genes and activate their transcription, resulting in maturation of the monocyte into a macrophage. In addition, these cellular factors activate the same AP-1 sequence in the visna virus LTR, leading to transcriptional activation, full viral gene expression, and production of progeny virus. The expression of viral antigens in the context of MHC class II on the macrophage leads to the production of cytokines and a lymphoproliferative response that causes the lesions in specific target organs in an infected animal. We still understand only the framework of these events. The specific mechanisms by which viral genes alter macrophage gene expression and the molecular basis of different viral tropism for specific tissue macrophages, i.e. microglia, remain to be determined.
One of the most important problems in tumor immunology studies is the in vivo role of natural killer (NK) cells and, as a consequence, the regulation of NK cell development and activity. It has been demonstrated that cells and soluble factors, including cytokines and hormones, are able to modulate NK activity by regulating both the reactivity of mature effector cells and the growth and differentiation of their precursors. One of the most interesting aspects of the in vitro generation of NK cells was the study of the role of different soluble factors, possibly involved in this process. In fact, while interleukin (IL)-2 was necessary for NK cell generation it is clear that other factors are involved in the first phase of differentiation and acquisition of IL-2-responsiveness. This suggests that, as in the rat, differentiation of mouse NK cells in addition to IL-2 needs other factors which are present in the CM.
The usual functional inhibition of medium-cultured monocytes by Lymphokine-activated killer (LAK) cells was reversed when the monocytes were cultured in IFN-g. Thus, the opposing effect of granulocyte macrophage-colony stimulating factor (GM-CSF) and IFN-g on monocyte functional susceptibility was similar to that found earlier on monocyte lysis by LAK cells. Antigen presentation is a sentinel process in the immune system. Monocytes take up antigen, process it and display an immunogenic fragment to lymphocytes, thereby delivering an activation signal to T cells. IFN-g protected monocytes from LAK suppression of antigen presentation. The opposing effects of GM-CSF and IFN-g on monocyte functional susceptibility, as measured by antigen presentation, were equivalent to those seen on monocyte antifungal activity. IFN-g protected monocytes from LAK suppression of antigen presentation. Monocytes are important accessory cells in the activation of T cells for specific antigen recognition and for control of microbial invasion.
This chapter investigates immediate effect of single and multiple UV treatments on susceptibility of MCA102 tumor cells to lysis by tumor necrosis factor and spleen cells. Natural cell-mediated immunity could play an important role in the elimination of tumor cells and preventing their local and metastatic growth. The efficiency of natural immunity was found also to be dependent on the level of tumor cell sensitivity to natural effector cells. The sensitivity of tumor cells to tumor necrosis factor (NK)- and tumor necrosis factor (NC) cell cytotoxicity varies in a broad range. Some tumor cells have preferential sensitivity to NK and other to NC cells. Several agents have been found to modify tumor cell sensitivity to natural cell-mediated cytotoxicity, but this effect is rather transient. In addition, same treatment could differently affect tumor cells sensitivity to NK or NC cells. UV irradiation induced some morphological changes in tumor cells. The original MCA102 and MCA105 tumor cells were strongly adherent fibroblast-like cells.
A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines, the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function, including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens, as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed, and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings, at dose ranges below those which are toxic (conventional maximal tolerable), are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines is a major focus of the Pittsburgh Cancer Institute. Regional delivery of cytokines such as interleukin-2 (IL-2) may be the most appropriate and least toxic approach, given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics, including bacillus Calmette-Guerin (BCG), IL-2, and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested, and trials are now in progress with IL-2 to assess the optimal dosage by this route. It is likely that the optimal role of IFN and other cytokines will be found in combination with one another, and with different biologic modalities such as monoclonal antibodies and vaccines, to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities, as well as anti-tumor effects, may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index.
There are two general concepts that we hope to have stressed concerning the recognition of microbes by phagocytic cells. The first is the concept of receptor redundancy and receptor cooperatively. Multiple receptors on leukocytes often participate in a given microbial recognition event. This concept can be illustrated by leishmania promastigotes that utilize both mannose receptors and Mac-1 to bind efficiently to macrophages. Likewise, macrophages use receptors for both IgG and complement to phagocytize encapsulated bacteria. This cooperativity between multiple receptors often changes the apparent affinity of the receptors for their ligand. Consequently the physiology of these receptors is altered. Fibronectin ligation, for example, results in the internalization of C3b-coated particles by the CR1. The second concept concerns the transduction of specific cellular signals following receptor ligation. Often, the receptor to which a microbe binds orchestrates many of the subsequent intracellular events during phagocytosis by transducing specific cellular signals. Some receptors, for example the mannose and Fc gamma-receptors, are particularly well suited to direct particles to phagolysosomes and trigger a respiratory burst, whereas other receptors, for example the CR1, may not. Indeed, from this perspective, one can view the immune response as being designed to target microbes preferentially to those receptors on phagocytic cells capable of making the appropriate cellular responses. In the case of leishmania, phagocytosis mediated by the Fc gamma receptors leads to parasite killing even by resident macrophages, while complement-mediated phagocytosis leads to parasite survival.
