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Co-stimulation Blockade Promotes Allogenic Stem Cell Therapy for Dysmyelination Disorders

Review of  “Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts” from Brain by Stuart P. Atkinson

Glial-restricted progenitors (GRPs) can differentiate into both oligodendrocytes and astrocytes, and previous studies have shown the ability of GRPs to preserve electrophysiological function following focal inflammatory spinal cord demyelination [1], support regeneration after spinal cord injury [2], replenish depleted precursor pools, generate new myelin, and reverse radiation-induced behavioral defects in adult rats [3]. However, their allogeneic application, the most clinically-relevant approach, requires demanding immunosuppression regimens to inhibit rejection and allow long-term survival and therapeutic function [4, 5].

In the search for a less demanding immunosuppressive option, researchers from the laboratory of Piotr Walczak (Johns Hopkins Medicine, Baltimore, MD, USA) now establish that a short-term co-stimulation blockade-based strategy to modulate T-cell activation allows the indefinite engraftment of GRP allografts in the mouse central nervous system. Furthermore, the team also identifies miRNAs that act as sensitive biomarkers for graft rejection/acceptance [6]. 

Are we one step closer to the successful application of allogenic GRPS in dysmyelination disorders?

Li et al. found that co-stimulation blockade, comprising CTLA4-Ig and anti-CD154 (MR-1) antibodies, prevented the rejection of allogeneic mouse GRPs after transplantation into immunocompetent mouse brains and allowed them to survive over the long-term (over 200 days). Histological analyses at the experimental endpoint found elaborate processes indicative of the maturation of grafted cells towards myelinating oligodendrocytes; however, this analysis failed to establish significant immune cell recruitment/infiltration. The subsequent evaluation of the mechanism behind the success of the co-stimulation blockade revealed that immunomodulation did not depend on regulatory T cells; instead, results indicated that the costimulation blockade mitigated the pro-inflammatory cytokine secretion profile induced by transplantation.

To assess the relevance of co-stimulation blockade as a treatment option for dysmyelination disorders, the authors transplanted mouse GRPs into the brains of adult myelin basic protein deficient, thus congenitally hypomyelinated, immunocompetent shiverer mice. Encouragingly, GRP transplantation alongside co-stimulation blockade increased the survival of mice, and the authors found evidence of potent myelination ability within a month after transplantation. 

In the final part of the study, the authors also identified a set of plasma miRNAs (including miR-146, miR-223, and let-7a/7c) whose levels correlate to changes in immunoreactivity, thereby representing potential biomarkers for graft rejection or tolerance

Overall, the authors provide evidence that co-stimulation blockade using CTLA4-Ig and anti-CD154 antibodies can inhibit allogeneic GRP rejection to allow subsequent survival and myelination/remyelination after transplantation into the brain, thereby representing an attractive option for patients with dysmyelinating diseases. Furthermore, their identification of plasma-borne miRNA biomarkers for allograft viability may represent a sensitive and relatively simple means to monitor cells grafted in a region inaccessible to conventional methods.

Are we one step further towards using allogeneic GRPs to enhance functional recovery in dysmyelination disorders in humans? Stay tuned to the Stem Cells Portal to find out!

References

  1. Walczak P, All AH, Rumpal N, et al., Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination. Glia 2011;59:499-510.
  2. Haas C and Fischer I, Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. Journal of Neurotrauma 2013;30:1035-52.
  3. Piao J, Major T, Auyeung G, et al., Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell 2015;16:198-210.
  4. Janowski M, Engels C, Gorelik M, et al., Survival of Neural Progenitors Allografted into the CNS of Immunocompetent Recipients is Highly Dependent on Transplantation Site. Cell Transplantation 2014;23:253-262.
  5. Srivastava AK, Bulte CA, Shats I, et al., Co-transplantation of syngeneic mesenchymal stem cells improves survival of allogeneic glial-restricted precursors in mouse brain. Experimental Neurology 2016;275 Pt 1:154-61.
  6. Li S, Oh BC, Chu C, et al., Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts. Brain 2019;142:3456-3472.