Abstract
How an antigen interacts differently with lymphocytes and other cells of the immune system, to result in the generation of distinct classes of immunity, is one of the most basic questions of immune regulation. Understanding the nature of these “decision criteria” is central to developing effective medical interventions. Clinical observations lead to the recognition that much disease is due to an inappropriate class of immunity being generated, inappropriate because damaging, as in autoimmunity and allergies, or inappropriate because ineffective, against pathogens and cancer. I argue that the prevalent, contemporary conceptual frameworks, employed to analyze the nature of the decision criterion controlling the Th1/Th2 phenotype of the immune response, are implausible, as they ignore pertinent, classical observations. I outline reasons for favoring a different framework, that takes these observations into account, and explore its pertinence to the design of strategies of medical intervention.
Highlights
Most cancers are progressive if the cytotoxic T lymphocyte (CTL) response is too weak, either because the cancer is insufficiently immunogenic [6], or because a substantial Th2 or other component of the response down-regulates the generation of CTL [7, 8]
We suggest the efficacy of this treatment is due to the fact that CD4 T cell depletion switches the anti-tumor response from a Th2 or Th1/Th2 toward a Th1 mode, as anticipated on the threshold mechanism
This finding is paradoxical for the pathogen-associated molecular patterns (PAMPs) and Cytokine Milieu Hypotheses
Summary
Older studies, initiated in the 1950s, characterized some variables of immunization that differentially affect the generation of DTH and IgG antibody production [14,15,16]. Mixed Th1/Th2 responses have intermediate correlates: poor DTH and, in the mouse, IgG2a and IgG1 antibody [17] and, in people, IgG1 and IgG2 antibody production [18] This context allows insights into how Th1 and Th2 cells are differentially generated. I describe three such variables, first characterized 40–60 years ago, and Abbreviations: APC, antigen presenting cells; CoS, costimulation/costimulatory; CMI, cell-mediated immunity; CTL, cytotoxic T lymphocytes; DTH, delayed-type hypersensitivity; PAMPs, pathogen-associated molecular patterns. Salvin showed that antigen dose, and time after immunization, affect the DTH/IgG antibody nature of the ensuing responses [14], see Figure 1A.
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