Some of the clearest evidence for direct White Blood Cell (WBC) involvement in tissue healing processes comes from the body of work generated by Michal Schwartz, an Israeli immunologist. For many years, even in the face of protracted skepticism, she single-mindedly worked with her team to develop and fine-tune rat and mouse models of acute CNS (Central Nervous System) injury and showed T cell and microglia/macrophage involvement in post-injury tissue healing, even in nerves. Her team showed
- Macrophages are involved in sciatic nerve regrowth: Macrophages cultured with segments of a nerve could stimulate nerve regrowth in transected rat optic nerve (1).
- CNS antigen-specific T cells are involved in rat optic nerve repair: Rat optic nerve crush injury model. Autoimmune T cells were protective towards injured neurons. When such cells were enriched in vitro and injected into rats subjected to optic nerve crush injury, macrophages, microglia and B cells increased in the vicinity of the injured optic nerve at greater numbers compared to those seen in non-T cell treated optic nerve-injured rats (2, 3).
- Microglia/macrophages are involved in injured retina repair: A neuroprotective role for microglia/macrophages in a mouse model of chemical-induced retinal injury (4). Microglia are CNS-resident macrophages.
- Myelin-specific T cells are involved in injured spinal cord repair (5, 6).
- Microglia/macrophages are involved in injured spinal cord repair (7, 8).
Other scientific teams have also shown immune cell-mediated tissue healing in a variety of animal models and tissues.
- Neuroprotective effects of T cells in a mouse model of chemical-induced demyelination (9).
- Monocytes supporting myogenesis after skeletal muscle injury in a mouse model (10).
- Microglia/macrophages are involved in injured spinal cord repair (11).
- Microglia help clean up dead photorecptor cells in retinal lesions without engaging in irreversible tissue damage (12).
- Activated rat macrophages induced by lens injury could promote post-optic nerve injury regeneration (13).
- Monocytes are involved in brain blood vessel repair (14).
How could such an immune cell-mediated process work?
Requires several notions antithetical to classic immune theory
- For one, requires tissue antigen-specific, i.e., self-specific, T cells. In the classic understanding, such self-specific T cells are inherently damaging so they are or need to be deleted from the T cell repertoire during their developmental phase in the thymus.
- For another, T cells inducing production of and microglia/macrophages producing specific tissue healing/regenerating substances such as doesn’t fit with the classic detect and defend formulation of immune functions.
Caveats to immune cell-mediated tissue healing models
- Artificial wound/injury models in rodents, data are mainly phenomenological, i.e., showing that a healing process is faster/improved in presence compared to absence of immune cells.
- Faster/improved healing process is assessed according to a highly subjective scoring scale. Such scoring scales are rather arbitrary, subject to change from one study to another and from one group of scientists to another. Poster child for flaws inherent to such models is the rodent model for multiple sclerosis (MS). Called EAE (Experimental Autoimmune Encephalitis), such models have been the mainstay of basic MS research and yet 40+ years and counting, hardly any workable therapeutics capable of treating/ameliorating MS have emerged from such studies.
- Not much success translating such rodent model observations to practical human therapies. For e.g., ex vivo activated autologous (isolated from patients themselves) macrophages didn’t promote substantial healing/repair in spinal cord injury patients (15). Why isn’t the science moving forward?
- Because cells involved in tissue healing processes, be they T cells, monocytes, macrophages, microglia (in the case of CNS), are inherently diverse (see figures below from 16). Currently accepted norms to characterize them are inadequate to accurately parse those with tissue-healing propensity away from those likely to damage. This being the current status quo, translational efforts to move immune cell-mediated tissue healing therapies into the clinic remain stuck in basic research mode.
The way academia is structured, going against the grain is very much uphill, if not outright impossible. Michal Schwartz had a few sources of leverage that likely helped her stay the course. Working in the tiny community of immunologists in the relatively small country of Israel, at a publicly funded institute,, marriage to a fellow scientist, Michael Eisenbach, these were a few of the tangible reasons she could stay the course in helping overturn some strongly held dogmas, namely, that
- Inflammation is injurious to tissue health.
- Typically using inflammation as defense to deter invaders, immune cells have little/no role in tissue healing.
1. Lazarov-Spiegler, O. R. L. Y., et al. “Transplantation of activated macrophages overcomes central nervous system regrowth failure.” The FASEB Journal 10.11 (1996): 1296-1302.
2. Barouch, Rina, and Michal Schwartz. “Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity.” The FASEB Journal 16.10 (2002): 1304-1306.
3. Moalem, Gila, et al. “Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy.” Nature medicine 5.1 (1999): 49-55.
4. London, Anat, et al. “Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages.” The Journal of experimental medicine 208.1 (2011): 23-39.
5. Ziv, Yaniv, et al. “Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury.” Proceedings of the National Academy of Sciences 103.35 (2006): 13174-13179.
6. Hauben, Ehud, et al. “Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens.” Proceedings of the National Academy of Sciences 98.26 (2001): 15173-15178.
7. Shechter, Ravid, et al. “Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.” (2009): e1000113.
8. Shechter, Ravid, et al. “Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus.” Immunity 38.3 (2013): 555-569.
9. Bieber, Allan J., Scott Kerr, and Moses Rodriguez. “Efficient central nervous system remyelination requires T cells.” Annals of neurology 53.5 (2003): 680-684.
10. Arnold, Ludovic, et al. “Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.” The Journal of experimental medicine 204.5 (2007): 1057-1069.
11. Zhu, Zhuangchen, et al. “NgR expression in macrophages promotes nerve regeneration after spinal cord injury in rats.” Archives of orthopaedic and trauma surgery 130.7 (2010): 945-951.
12. Joly, Sandrine, et al. “Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions.” The American journal of pathology 174.6 (2009): 2310-2323.
13. Yin, Yuqin, et al. “Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells.” Nature neuroscience 9.6 (2006): 843-852.
14. Glod, John, et al. “Monocytes form a vascular barrier and participate in vessel repair after brain injury.” Blood 107.3 (2006): 940-946.
15. Lammertse, D. P., et al. “Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial.” Spinal Cord 50.9 (2012): 661-671.
16. Kokaia, Zaal, et al. “Cross-talk between neural stem cells and immune cells: the key to better brain repair [quest].” Nature neuroscience 15.8 (2012): 1078-1087.