Anti‐CD52 blocks EAE independent of PD‐1 signals and promotes repopulation dominated by double‐negative T cells and newly generated T and B cells

Abstract

Lymphocyte depletion using anti‐CD52 antibody effectively reduces relapses of multiple sclerosis (MS). To begin to understand what mechanisms might control this outcome, we examined the effect of a murine‐CD52‐specific mAb on the depletion and repopulation of immune cells in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We tested whether the tolerance‐promoting receptor programmed cell death protein‐1 (PD‐1) is required for disease remission post anti‐CD52, and found that PD‐1‐deficient mice with a more severe EAE were nevertheless effectively treated with anti‐CD52. Anti‐CD52 increased the proportions of newly generated T cells and double‐negative (DN) T cells while reducing newly generated B cells; the latter effect being associated with a higher expression of CD52 by these cells. In the longer term, anti‐CD52 caused substantial increases in the proportion of newly generated lymphocytes and DN T cells in mice with EAE. Thus, the rapid repopulation of lymphocytes from central lymphoid organs post anti‐CD52 may limit further disease. Furthermore, these data identify DN T cells, a subset with immunoregulatory potential, as a significant hyperrepopulating subset following CD52‐mediated depletion.

The Meaning of Immune Reconstitution after Alemtuzumab Therapy in Multiple Sclerosis

“…Moreover, recent findings show that also CD8 double-negative (DN) T cells are hyper-repopulated after alemtuzumab treatment in EAE mice. DN T cells have frequently been associated with suppression of immune responses, highlighting another possible mechanism to suppress autoimmunity beside the action of Treg cells [22].…”

Loss of thymic function promotes EAE relapse in anti-CD52-treated mice

“…EAE was induced and scored as previously described ( Haile et al, 2020 ) using MOG 35–55 peptide in complete Freund's adjuvant and pertussis toxin. EAE disease was scored as 0 = no signs, 1 = paralyzed tail, 2 = hindlimb weakness, 3 = paralysis of both hindlimbs, 4 = paralysis of both hindlimbs and weakness of one forelimb, 5 = moribund.…”

“…The hematopoietic stem cells and lymphocyte precursor cells lack CD52, thereby providing the potential for lymphocyte repopulation from precursors after anti-CD52 therapy. We recently showed that immune system reset with anti-CD52 promotes lymphocyte repopulation that is initially dominated by double-negative T cells and newly generated T and B cells ( Haile et al, 2020 ). The rapid repopulation of the peripheral lymphoid niche with newly generated T cells in mice with EAE treated with anti-CD52 suggested a possible explanation for the variable efficacy of anti-CD52 in humans ( Cohen et al, 2012 ; Haile et al, 2020 ; Turner et al, 2015 ; Ziemssen and Thomas, 2017 ) compared to the near-complete effectiveness in mice.…”

“…We recently showed that immune system reset with anti-CD52 promotes lymphocyte repopulation that is initially dominated by double-negative T cells and newly generated T and B cells ( Haile et al, 2020 ). The rapid repopulation of the peripheral lymphoid niche with newly generated T cells in mice with EAE treated with anti-CD52 suggested a possible explanation for the variable efficacy of anti-CD52 in humans ( Cohen et al, 2012 ; Haile et al, 2020 ; Turner et al, 2015 ; Ziemssen and Thomas, 2017 ) compared to the near-complete effectiveness in mice. In humans, repopulation of T cells post anti-CD52 is extremely slow, particularly for CD4 T cells (>2 years to recover), while repopulation in mice occurs within several weeks ( Haile et al, 2020 ; Hill-Cawthorne et al, 2012 ).…”

“…The rapid repopulation of the peripheral lymphoid niche with newly generated T cells in mice with EAE treated with anti-CD52 suggested a possible explanation for the variable efficacy of anti-CD52 in humans ( Cohen et al, 2012 ; Haile et al, 2020 ; Turner et al, 2015 ; Ziemssen and Thomas, 2017 ) compared to the near-complete effectiveness in mice. In humans, repopulation of T cells post anti-CD52 is extremely slow, particularly for CD4 T cells (>2 years to recover), while repopulation in mice occurs within several weeks ( Haile et al, 2020 ; Hill-Cawthorne et al, 2012 ). This creates a long-term state of lymphopenia in the human setting ( Jones et al, 2013 ) that does not typically occur in the mouse.…”