Mutation selection for immune response to MBP in HAM/TSP

University Of Vermont &St Agric College, Burlington VT

Investigators

Abstract

DESCRIPTION (provided by applicant): Human T-cell lymphotropic virus type I (HTLV-1) is a human retrovirus that infects approximately 10 million people worldwide. The majority of infected individuals remain healthy lifelong asymptomatic carriers (ACs); approximately 0.25% to 3% develop an inflammatory disease of the central nervous system termed HTLV-1- associated myelopathy/tropical spastic paraparesis (HAM/TSP), and another 2% to 3% develop an aggressive mature T-cell malignancy termed adult T-cell leukemia (ATL). The virus is endemic throughout Japan, with certain regions of the country having elevated prevalence rates. Because such a large number of people are carders of this potentially devastating virus, developing an effective measure to control the endemic cycle of HTLV-1 has been imperative. Since the clinical findings in HAM/TSP resemble the clinical picture of multiple sclerosis (MS), an understanding of the neuropathogenesis of a disease with a known viral etiology may provide insights into mechanisms of pathogenesis in an autoimmune disease of unknown etiology. This is particularly relevant since T cell receptor (TCR) sequences derived from spinal cord lesions from HAM/TSP patients show similarity to TCRs from myelin basic protein (MBP)-reactive T-cells, TCRs detected within the brain lesions of MS patients, and encephalitogenic T-cell clones from rodents with experimental autoimmune encephalomyelitis. We have observed similar TCR sequences from HAMFFSP patients using a method of isolating T cells that have undergone extensive in vivo cell division. The method involves detecting cells with mutations in a selectable reporter gene, and has been used to demonstrate the presence of in vivo activated T cells responsive to MBP in MS patients. The approach may be useful for addressing a variety of questions in human immunology. The goal of this proposal is to demonstrate that the reporter gene-selected T cells from HAM/TSP patients respond to MBP much like their counterparts derived from MS patients, indicating similar pathogenic mechanisms for the two diseases. The long-term goal of the project would be to broaden the applicability of this approach for the study of other human immune responses, particularly in autoimmune disease and cancer, where an understanding of detrimental and beneficial immune responses can ultimately translate into improved treatment options based on new immunotherapeutic approaches.