Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis

Abstract

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.

How do immune cells overcome the blood–brain barrier in multiple sclerosis?

“…Interestingly, while ICAM‐1 expression is associated with infiltration of inflammatory T cells during early lesion formation in experimental autoimmune encephalitis (EAE), it is also involved in the migration of anti‐inflammatory and protective regulatory T lymphocytes into the CNS. ICAM‐1 early blockade therefore improves clinical and pathological indices of EAE, but a late blockade worsens it, outlining the complexity of leukocyte‐BBB interactions and the potential beneficial effects of the so‐called pro‐inflammatory cytokines [70].…”

Changes in CD200 and intercellular adhesion molecule-1 (ICAM-1) levels in brains of Lewy body disorder cases are associated with amounts of Alzheimer's pathology not α-synuclein pathology

“…In AD-affected brains, ICAM-1 immunoreactivity was associated with plaques, and astrocytes surrounding plaques (Akiyama et al, 1993; Eikelenboom et al, 1994; Frohman et al, 1991; Verbeek et al, 1994), while in PD-affected brains, there was increased immunoreactivity for ICAM-1 in microglia and astrocytes (Imamura et al, 2003; Miklossy et al, 2006). Increased expression of ICAM-1 on cerebral vascular endothelial cells is also a feature of inflammation in brain tissue (Doerck et al, 2010). …”

ssICAM-1, IL-21 and IL-23 in patients with tick borne encephalitis and neuroborreliosis

“…Doerck et al suggest, that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the BBB is time related and could result in different therapeutic outcomes depending on the phase of CNS lesion development [12].…”