A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

Abstract

SummaryThe development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic-relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-99) and myelin oligodendrocyte g|yco-protein (MOG 92-106) at various times after induction of EAE in (SWRXSJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattem. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 173-198 were sequentially accumulated in all mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (S'W~• 1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction ofpeptidespecific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self-determinant recognition provides a basis for sequential determinant-specific therapeutic intervention after onset of the autoimmune disease process.

Coronary Arteries from Human Cardiac Allografts with Chronic Rejection Contain Oligoclonal T Cells: Persistence of Identical Clonally Expanded TCR Transcripts from the Early Post-Transplantation Period (Endomyocardial Biopsies) to Chronic Rejection (Coronary Arteries)

“…Another possible explanation, particularly in the case of CNS demyelinating disease, is de novo priming of self-reactive T cells to sequestered (auto)Ag epitopes released as a result of the primary immune response. However, there is a significant difference between epitope spreading in chronic rejection (71,72) and that in demyelinating diseases (73)(74)(75)(76)(77). To date, all epitope spreading responses in chronic rejection are recognizing allogeneic HLA-DR epitopes, dominant or cryptic, but do not recognize self-determinants (71,72).…”

“…Intermolecular and intramolecular epitope spreading has been demonstrated in the proliferative responses of PBMC to synthetic peptides of the hypervariable region of 32 HLA-DR alleles (71,72). Epitope spreading has been originally described in autoimmune demyelinating diseases of the CNS (73)(74)(75)(76)(77), and it is defined as the generation of de novo immune responses to epitopes different from and noncross-reacting to those that initially induced the immune response. This definition (73)(74)(75)(76)(77) is extended now to the immunity against grafts (71,72) and to the immunity against tumors (78).…”

“…Epitope spreading has been originally described in autoimmune demyelinating diseases of the CNS (73)(74)(75)(76)(77), and it is defined as the generation of de novo immune responses to epitopes different from and noncross-reacting to those that initially induced the immune response. This definition (73)(74)(75)(76)(77) is extended now to the immunity against grafts (71,72) and to the immunity against tumors (78). Progression to chronicity in demyelinating autoimmune disorders and in graft rejection is associated with broadening the T cell repertoire with time (79).…”

Proinsulin: a unique autoantigen triggering autoimmune diabetes

“…In 1990, TSP1 was first described as an inhibitor of angiogenesis, as it blocked the formation of new blood vessels in the cornea in vivo in response to basic FGF (1,3) and blocked endothelial cell tube formation and cell migration in vitro (2). Additional studies showed that TSP1 could serve as a naturally occurring tumor suppressor by inhibiting tumor angiogenesis (3).…”

“…Early developments in the field of angiogenesis research led to the discovery of many angiogenesis-stimulating factors, including the well-known VEGF, and to the discovery of naturally occurring angiostatic agents, such as the thrombospondins (TSPs) (1-3). TSP1 was the first naturally arising angiogenesis inhibitor to be described (1)(2)(3). Shortly thereafter, a second TSP, TSP2, was also found to inhibit angiogenesis (4).…”