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

A healthy immune system: the ultimate balancing act

   Our immune system is the intricate network of cells, tissues, and their secretions that help the body fight illness and infection. The immune system is comprised of two branches, the innate and the adaptive immune responses. The innate immune response is the first line of defense that immediately works to prevent the spread of pathogens and tumors,¹ while the adaptive immune response is a specialized, secondary response for clearing specific pathogens.²

The efficacy of these two systems depends on a well-balanced inflammatory and anti-inflammatory response, known as immunomodulation. Upon injury or infection, macrophages of the innate immune system phagocytose, or engulf, damaged tissue and foreign pathogens while simultaneously secreting molecules that promote inflammation. These pro-inflammatory molecules dilate blood vessels and recruit immune cells to the damaged site. While inflammation is initially beneficial, the immune system must also mount an anti-inflammatory, reparatory response once the infection is cleared.

Age-dependent immune dysregulation

Immune dysfunction is at the root of age-related diseases.³ Over time, the body’s cells accumulatemolecular damage, and immune cells are no exception. The affected immune cells no longer respond appropriately to the complex regulatory signals of their environment. The balance between inflammatory and anti-inflammatory responses is lost, in favor of chronic, low-level inflammation that increases our vulnerability to age-associated disorders.⁴

The hostile inflammatory environment releases secretions that recruit more inflammatory cells, resulting in progressive exhaustion of the immune system known as inflammaging. Inflammagingexacerbates conditions like age-related muscle atrophy, or sarcopenia, which occurs in 100% of individuals.⁵With inflammaging, immune cells can no longer maintain repair of the everyday wear and tear of muscle tissue. 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 age-dependent diseases.⁶

The secrets of the secretome

The secretome is the total set of substances secreted by a cell including proteins, lipids, growth factors, chemokines, cytokines, exosomes, and microvesicles.⁷ The secretome provides essential intracellular communication between cells. 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. Cells that have already become specialized and committed to a particular biological function such as a retinal cell, or in which the regenerative capabilities are lost, are less likely to provide these same benefits.

As we age, we lose the ability to produce new stem cells efficiently and thus, we lose the benefits of the stem cell secretome. One approach is to replenish tissues with regenerative stem cells, but the practical implementation of such therapies faces a history of challenges in manufacturing, tumorigenicity, allogeneic incompatibility.⁸ Secretomes may provide an alternative therapeutic approach because the bioactive molecules could yield immediate therapeutic benefits to restore the regenerative stem cell niche long-term.

Research on secretome therapies has been on the rise since 2009 because they minimize the risk of immune system rejection and avoid tumorgenicity.⁹ Other advantages of secretomes include cost-effective manufacturing and scalability for mass production.⁸ Lastly, the secretome has multiple methods of administration (ie. injection, topical, inhalation), enabling treatment versatility.⁸ Secretomes provide incredible therapeutic advantages over traditional stem cell-based therapies and may be an ideal solution.

Immune balance via the secretome

Immune system function is the most critical determinant of quality of life as we age. How can we avoid our immune system’s demise? Immunomodulation may be the answer. Immunomodulation uses compounds to either activate or inactivate specific immune cell responses. Believe it or not, you have already consumed immunomodulators if you have ever taken an aspirin. Research suggests that low-dose aspirin can decrease inflammatory markers like NF-kB in the blood. Thus, immunomodulators like aspirin may help lower the risk of inflammatory-associated diseases such as heart disease and type 2 diabetes.^10–12

Evidence suggests that the secretome is also involved in immunomodulation, which may make it an effective therapeutic for autoimmune diseases, neurodegenerative diseases and sarcopenia.^13,14 Everyone develops sarcopenia over time, which significantly compromises quality of life; and mitigating muscle loss and improving muscle recovery are unfulfilled medical needs. Preclinical data using Immunis’ investigational secretome product demonstrated immunomodulatory and regenerative capabilities. In aged mouse-models of muscle disuse and atrophy, Immunis’ investigational secretome increased the number of muscle stem cells, enhanced muscle size, elevated the number of reparatory immune cells, and improved muscle strength.¹⁵ Immunis is currently conducting an FDA-approved Phase 1/2a clinical trial in aged patients with knee osteoarthritis-related muscle deterioration to research the safety and tolerability of this investigational secretome.¹⁶ Companies like Immunis are paving the way for addressing inevitable, age-related diseases that are currently untreatable.

The secretome is a powerful tool in biomedicine with endless potential. In understanding that a well-functioning immune system is necessary for our health and that secretomes can refine immune cell responses, 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)         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.

(9)         Pinho, A. G.; Cibrão, J. R.; Silva, N. A.; Monteiro, S.; Salgado, A. J. Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders. Pharmaceuticals 2020, 13 (2), 31. https://doi.org/10.3390/ph13020031.

(10)      Kopp, E.; Ghosh, S. Inhibition of NF-Kappa B by Sodium Salicylate and Aspirin. Science 1994, 265 (5174), 956–959. https://doi.org/10.1126/science.8052854.

(11)      Grilli, M.; Pizzi, M.; Memo, M.; Spano, P. Neuroprotection by Aspirin and Sodium Salicylate through Blockade of NF- ΚB Activation. Science 1996, 274 (5291), 1383–1385. https://doi.org/10.1126/science.274.5291.1383.

(12)      Lin, M.-H.; Lee, C.-H.; Lin, C.; Zou, Y.-F.; Lu, C.-H.; Hsieh, C.-H.; Lee, C.-H. Low-Dose Aspirin for the Primary Prevention of Cardiovascular Disease in Diabetic Individuals: A Meta-Analysis of Randomized Control Trials and Trial Sequential Analysis. J. Clin. Med. 2019, 8 (5), 609. https://doi.org/10.3390/jcm8050609.

(13)      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.

(14)      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.

(15)      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.

(16)      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).