Written and Illustrated by Karissa Jade Muñoz, Ph.D.

Maintaining Immune Health: A Delicate Act of Balance

The immune system encompasses innate and adaptive immune responses, both of which are crucial in maintaining our health. The innate immune response is the first line of defense that quickly works to prevent the spread of pathogens and tumors.¹ The adaptive immune response is more sophisticated and specialized secondary response that clears specific pathogens and provides long-lasting immunity.² The efficacy of these two systems depends on balanced inflammatory and anti-inflammatory responses referred to as immunomodulation.

Immune dysregulation with age

As people age, so does their immune system, meaning it doesn’t function as effectively as it used to. Aging causes a time-dependent accumulation of molecular and cellular damage to our immune cells. Immune senescence is when these immune cells no longer respond appropriately to the complex regulatory signals of their environment, resulting in an imbalance of inflammatory and anti-inflammatory responses.³Immune dysregulation increases our vulnerability to age-associated disorders.⁴

A manifestation of immune senescence is inflammaging, which is the accumulation of low-grade inflammation, resulting in toxic cellular secretions that affect local and distant organs.⁴ These persistent damage signals create a hostile extracellular environment that damages cells and progressively exhausts the immune system. Age-related muscle atrophy, or sarcopenia, occurs in 100% of individuals and is exacerbated by inflammaging.⁵ The immune cells that once repaired the everyday wear and tear of muscle tissue no longer maintain these restorative functions later in life. Additionally, almost all age-related diseases such as arthritis, Alzheimer’s, atherosclerosis, diabetes, sarcopenia, and cancer have an immune deterministic component, suggesting that preserving immune system function may prevent all age-dependent diseases.⁶

The secrets of the secretome

The secretome is the total set of proteins, lipids, growth factors, chemokines, cytokines, exosomes, and molecules secreted by a cell.⁷ The secretome orchestrates complex cellular interactions and is highly variable depending on the environmental conditions and cell type from which it arises.⁸ Regenerative niches containing stem cells such as mesenchymal stem cells and multi/pluripotent stem cells produce secretomes with anti-inflammatory, anti-apoptotic, and immunomodulatory properties. Tissues that contain specialized cells committed to a particular biological function, such as a retinal cell, are less likely to provide these same benefits.

As we age, not only do we lose the capacity to efficiently produce new stem cells, but we also lose the benefits of their secretome. One approach is to replenish tissues with regenerative stem cells. However, the practical implementation of these therapies faces a long history of challenges such as manufacturing, tumorigenicity, and allogeneic incompatibility.⁹

The secretome is being studied as an alternative therapeutic approach to stem cells because the secreted bioactive molecules, and not the stem cells themselves, would yield the immediate therapeutic benefits. Secretome-based therapies provide a natural, cell-free method to combating disease, thereby minimizing the risk of immune system rejection and avoiding tumorgenicity. Also, the secretome has multiple methods of administration including injection, inhalation, and as a topical, providing versatile treatment applications.⁹ The secretome provides incredible therapeutic advantages over traditional stem cell-based therapies and offers another treatment option in the field of biomedicine.

The potential of the secretome in restoring immune balance 

Our immune system is the most critical determinant of our health, affecting our susceptibility to disease and ultimately, quality of life as we age. But how do we regulate our immune system function to circumvent its demise?

Immunomodulation is the use of compounds to either activate or inactivate specific immune cell responses. Believe it or not, immunomodulators exist all around us. Chances are you’ve consumed immunomodulators in your coffee if you added milk. Vitamin D has been shown to increase the phagocytic ability of innate immune cells and produce anti-inflammatory effects.¹⁰ Chronic conditions with higher levels of inflammation such as diabetes, asthma, and rheumatoid arthritis are all associated with vitamin D deficiency, suggesting the importance of specific immunomodulators in preventing disease.

Evidence suggests that the secretome is also involved in immunomodulation, which may make it an effective therapeutic for autoimmune diseases, neurodegenerative diseases, and sarcopenia.^11,12 As mentioned, all humans develop sarcopenia with age, which significantly impairs mobility and compromises quality of life. Mitigating muscle loss and improving muscle recovery are currently unfulfilled medical needs. Preclinical data using Immunis’ investigational secretome product from partially differentiated stem cells demonstrated immunomodulatory and regenerative capabilities in aged mouse-models of muscle disuse and atrophy.¹³ Immunis is currently conducting an FDA-approved Phase 1/2a clinical trial in aged patients with muscle atrophy associated with knee osteoarthritis to research the safety and tolerability of our investigational secretome.¹⁴ Companies like Immunis are paving the way for addressing inevitable and currently, untreatable age-related diseases.

The secretome has endless potential as a tool in biomedicine. A well-functioning immune system is necessary for our health and secretomes can refine immune cell responses, meaning the immunomodulatory power of the secretome can drastically reduce susceptibility to disease.

Perhaps the secret to longevity is the secretome!

References:

(1)         Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. Innate Immunity. Mol. Biol. Cell 4th Ed. 2002.

(2)         Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. The Adaptive Immune System. Mol. Biol. Cell 4th Ed.2002.

(3)         Isobe, K.; Nishio, N.; Hasegawa, T. Immunological Aspects of Age-Related Diseases. World J. Biol. Chem. 2017, 8 (2), 129–137. https://doi.org/10.4331/wjbc.v8.i2.129.

(4)         Fulop, T.; Larbi, A.; Dupuis, G.; Le Page, A.; Frost, E. H.; Cohen, A. A.; Witkowski, J. M.; Franceschi, C. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front. Immunol. 2018, 8.

(5)         Liang, Z.; Zhang, T.; Liu, H.; Li, Z.; Peng, L.; Wang, C.; Wang, T. Inflammaging: The Ground for Sarcopenia? Exp. Gerontol.2022, 168, 111931. https://doi.org/10.1016/j.exger.2022.111931.

(6)         Kalyani, R. R.; Corriere, M.; Ferrucci, L. Age-Related and Disease-Related Muscle Loss: The Effect of Diabetes, Obesity, and Other Diseases. Lancet Diabetes Endocrinol. 2014, 2 (10), 819–829. https://doi.org/10.1016/S2213-8587(14)70034-8.

(7)         Xia, J.; Minamino, S.; Kuwabara, K.; Arai, S. Stem Cell Secretome as a New Booster for Regenerative Medicine. Biosci. Trends 2019, 13 (4), 299–307. https://doi.org/10.5582/bst.2019.01226.

(8)         Shin, J.; Rhim, J.; Kwon, Y.; Choi, S. Y.; Shin, S.; Ha, C.-W.; Lee, C. Comparative Analysis of Differentially Secreted Proteins in Serum-Free and Serum-Containing Media by Using BONCAT and Pulsed SILAC. Sci. Rep. 2019, 9, 3096. https://doi.org/10.1038/s41598-019-39650-z.

(9)         Li, F.; Zhang, J.; Yi, K.; Wang, H.; Wei, H.; Chan, H. F.; Tao, Y.; Li, M. Delivery of Stem Cell Secretome for Therapeutic Applications. ACS Appl. Bio Mater. 2022, 5 (5), 2009–2030. https://doi.org/10.1021/acsabm.1c01312.

(10)      Sassi, F.; Tamone, C.; D’Amelio, P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients 2018, 10 (11), 1656. https://doi.org/10.3390/nu10111656.

(11)      Teixeira, F. G.; Carvalho, M. M.; Panchalingam, K. M.; Rodrigues, A. J.; Mendes‐Pinheiro, B.; Anjo, S.; Manadas, B.; Behie, L. A.; Sousa, N.; Salgado, A. J. Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson’s Disease. Stem Cells Transl. Med. 2017, 6 (2), 634–646. https://doi.org/10.5966/sctm.2016-0071.

(12)      Tidball, J. G.; Flores, I.; Welc, S. S.; Wehling-Henricks, M.; Ochi, E. Aging of the Immune System and Impaired Muscle Regeneration: A Failure of Immunomodulation of Adult Myogenesis. Exp. Gerontol. 2021, 145, 111200. https://doi.org/10.1016/j.exger.2020.111200.

(13)      Fix, D. K.; Mahmassani, Z. S.; Petrocelli, J. J.; de Hart, N. M. M. P.; Ferrara, P. J.; Painter, J. S.; Nistor, G.; Lane, T. E.; Keirstead, H. S.; Drummond, M. J. Reversal of Deficits in Aged Skeletal Muscle during Disuse and Recovery in Response to Treatment with a Secrotome Product Derived from Partially Differentiated Human Pluripotent Stem Cells. GeroScience 2021, 43 (6), 2635–2652. https://doi.org/10.1007/s11357-021-00423-0.

(14)      Immunis, Inc. An Open-Label Dose Escalation Study to Assess the Safety and Tolerability of IMM01-STEM in Participants With Muscle Atrophy Related to Knee Osteoarthritis; Clinical trial registration NCT05211986; clinicaltrials.gov, 2022. https://clinicaltrials.gov/ct2/show/NCT05211986 (accessed 2023-01-30).