Islet cell
antigen p69 (ICA69) is a target
autoantigen in
IDDM. Studies of T-cells from newly diabetic children suggested possible antigenic mimicry between human ICA69 (in particular the Tep69
T-cell epitope, aa 36-47) and the
ABBOS region in
bovine serum albumin (BSA; aa 152-169), one of several cow's milk
proteins that evoke abnormal immunity in diabetes-prone hosts. We recently found the sequence of Tep69 regions to be identical in the four alternatively spliced human and rodent ICA69
isoforms. Immunization of nonobese diabetic (NOD) mice with BSA or ICA69 generates fully cross-reactive T-cell responses to both Tep69 and
ABBOS as the immunodominant, naturally generated, and presented T-cell mimicry
epitopes. Such responses are absent or weak in healthy strains of mice. NOD mouse recipients of adoptive spleen cell grafts from diabetic donors spontaneously generate easily detectable pools of T-cells specific for ICA69/BSA, as well as the unrelated GAD65. NOD mice injected neonatally with
ABBOS or Tep69 show cross-tolerance, but
ABBOS-induced tolerance is transient. Neonatal injection of Tep69 reduces disease incidence (23 vs. 68%
IDDM, P < 0.02), while neonatal injection of
ABBOS has little effect. In contrast, systemic immunization of young NOD females with
ABBOS (but not Tep69) reduces the diabetes incidence and delays disease expression, with protected mice generating
ABBOS-specific T-cell repertoires unable to recognize the Tep69 mimicry antigen. Our observations demonstrate a loss of self-tolerance to ICA69 in NOD mice, and they establish antigenic mimicry between the two
T-cell epitopes in ICA69 and BSA. Further studies are necessary to understand the molecular basis of this mimicry and how either T-cell
peptide can modify the disease course.