Rationalizing the path to a universal graft recipient
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INTERPRETIVE SYNTHESIS REVIEW ARTICLE
Rationalizing the path to a universal graft recipient Melvin Cohn 1
# Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract The goal of this essay is to take the reader through the logic that would predict universal graft acceptance. The story begins with what we learned from an experiment performed 65 years ago and develops that information in greater depth. The pathway of the analysis leads to the conclusion that controlling the immune system at the level of the T-helper would be the best way to approach a general solution to the problem of graft acceptance. Keywords Tissue transplantation . Chimerism . TCR structure-function . Suppression
Abbreviations APC Antigen presenting cell ARA Associative (linked) Recognition of Antigen BCR B cell antigen receptor TCR T cell antigen receptor Tsu Suppressor T cell eTh Effector T-helper eTsu Effector suppressor T cell GvHD Graft vs host disease MHC Major histocompatibility complex S-NS Self-Nonself
Background
Introduction
It is because the virgin recognitive repertoire is vast and random (module 1) that it must be sorted (module 2). We refer to the sorting process as the Self(S)-Nonself(NS) discrimination. Induction of effector function (module 3) requires that its magnitude be controlled. This is the role of feedback suppression. A runaway effector response leads to innocent bystander immunopathology, which must be distinguished from autoimmunity. All three modules have solid conceptual bases. For our discussion here, only modules 2 and 3 are considered. Module 2, the S-NS discrimination, is best analyzed by the Associative (linked) Recognition of Antigen Model (ARA) [2–5] which is a correction and extension of our original two signal models [6]. The core principle for this discussion is that the interaction of the antigen-receptor on the naïve T or B cell with ligand (signal 1) is deletional (negative selection). The activation of the cell receiving signal 1 requires a second signal (signal 2) delivered by an effector T-helper (eTh) in ARA.
Transplantation immunology has a long and rich history of experiment [1]. It lacks a conceptual base, relying almost completely on empiricism. For this reason, important observations have been treated simply as facts, and allowed to accumulate to become a vast complex subject. By mapping the facts onto a coherent understanding of immune responsiveness, the pathway that arrives at a universal graft recipient, is suggested.
* Melvin Cohn [email protected] 1
Conceptual Immunology Group, The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA
The adaptive immune system can be divided into three modules that are interconnected but definably distinguished because each module has a distinct database and rationale. The three modules are the following: 1. The generation of the recognitive repertoire 2. The purging of anti-Self from the repertoire leaving antiNonself; this is a somatically encoded learning process. 3. The regulation of the choice and magnitude of t
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