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

A healthy immune system: the ultimate balancing act

The immune system is comprised of 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 immediately works to prevent the spread of pathogens and tumors.¹ The adaptive immune response is a more sophisticated, secondary response that is specialized to clear specific pathogens and provide long-lasting immunity.²

The efficacy of these two systems depends on balanced inflammatory and anti-inflammatory responses, referred to as immunomodulation. For example, upon injury or infection, macrophages secrete molecules that promote inflammation to dilate blood vessels and recruit other immune cells to the damaged site. Once the infection is cleared, the immune system mounts an anti-inflammatory, reparatory response.

Age-dependent immune dysregulation

As people age, so does their immune system, meaning it no longer functions as effectively. Aging allows the time-dependent accumulation of molecular damage to our immune cells, which causes them to respond inadequately to external, regulatory signals. The result is immune dysregulation of inflammatory and anti-inflammatory responses and increased vulnerability to age-associated disorders.^3,4

Inflammaging is the progressive accumulation of low-grade inflammation.³ These persistent inflammatory signals are damaging and create a hostile extracellular environment. 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 age-dependent diseases.⁶

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 promotes interactions between cells when resolving an infection. However, defining the specific secretome factors that combat disease remains a challenge.⁸

The secretome is highly dependent on the environmental conditions and cell type,⁹ meaning not all secretomes are the same. Regenerative niches containing stem cells such as mesenchymal stem cells and multi/pluripotent stem cells produce secretomes that demonstrate 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 in manufacturing, tumorigenicity, and allogeneic incompatibility.¹⁰

The secretome is being studied as an alternative therapeutic approach to stem cells because it is the secreted bioactive molecules, and not the stem cells themselves, that 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 can be administered by injection, inhalation, or topically, providing versatile treatment applications.¹⁰ The secretome provides incredible therapeutic advantages over traditional stem cell-based therapies and offers another treatment option in the field of biomedicine.

Immunomodulation via the secretome

Our immune system is the most critical determinant of our health, affecting our susceptibility to disease and ultimately, quality of life as we age. 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 responses. Immunomodulators exist all around us. You have likely consumed immunomodulators in your coffee if you added milk. Vitamin D increases innate immune cell function and has anti-inflammatory effects.¹¹ Chronic conditions with high 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.

The secretome is also proposed to be involved in immunomodulation,^12,13 which is an area of research being explored by the biotechnology company, Immunis. 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.¹⁴ 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 the investigational secretome.¹⁵ 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)         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.

(4)         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.

(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)         Phelps, J.; Sanati-Nezhad, A.; Ungrin, M.; Duncan, N. A.; Sen, A. Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics. Stem Cells Int. 2018, 2018, e9415367. https://doi.org/10.1155/2018/9415367.

(9)         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.

(10)      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.

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

(12)      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.

(13)      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.

(14)      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.

(15)      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).