Biology:T-cell depletion

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T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its responses. Depletion can occur naturally (i.e. in HIV) or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958.[1] In humans the first TCD was performed in severe combined immunodeficiency patients.[2][3]

Depletion methods

T cell depletion methods can be broadly categorized into either physical or immunological. Examples of physical separation include using counterflow centrifugal elutriation, fractionation on density gradients, or the differential agglutination with lectins followed by rosetting with sheep red blood cells. Immunological methods utilize antibodies, either alone, in conjunction with homologous, heterologous, or rabbit complement factors which are directed against the T cells. In addition, these techniques can be used in combinations.[4][3]

These techniques can be performed either in vivo, ex vivo, or in vitro.[3] Ex vivo techniques enable a more accurate count of the T cells in a graft and also has the option to 'addback' a set number of T cells if necessary. Currently, ex vivo techniques most commonly employ positive or negative selection methods using immunomagnetic separation. In contrast, in-vivo TCD is performed using anti-T cell antibodies or, most recently, post-HSCT cyclophosphamide.[5]

The method by which depletion occurs can heavily affect the results. Ex vivo TCD is predominantly used in GVHD prevention, where it offers the best results.[6] However, complete TCD via ex vivo, especially in acute myeloid leukemia (AML), patients usually does not improve survival.[7] In vivo depletion often uses monoclonal antibodies (eg, alemtuzumab) or heteroantisera.[7] In haploidentical hematopoietic stem cell transplantation, in vivo TCD suppressed lymphocytes early on. However, the incidence rate of cytomegalovirus (CMV) reactivations is elevated. These problems can be overcome by combining TCD haploidentical graft with post-HSCT cyclophosphamide.[8] In contrast, both in vivo TCD with alemtuzumab and in vitro TCD with CD34+ selection performed comparably.[9]

Although TCD is beneficial to prevent GVHD there are some problems it can cause a delay in recovery of the immune system of the transplanted individual and a decreased Graft-versus-tumor effect. This problem is partially answered by more selective depletion, such as depletion of CD3+ or αβT-cell and CD19 B cell, which preserves other important cells of the immune system.[10] Another method is addition of cells back into the graft, after a comprehensive TCD method, examples are re-introduction of natural killer cells (NK), γδ T-cells[11] and T regulatory cells (Tregs).[12]

Early on it was apparent that TCD was good for preventing GVHD, but also led to increased graft rejection, this problem can be solved by transplanting more hematopoietic stem cells. This procedure is called 'megadose transplantation' and it prevents rejection because the stem cells have an ability (i.e. veto cell killing) to protect themselves from the host's immune system.[13] Experiments show that transplantation of other types of veto cells along with megadose haploidentical HSCT allows to reduce the toxicity of the conditioning regimen, which makes this treatment much safer and more applicable to many diseases.[14][15] These veto cells can also exert graft vs tumor effect.[16]

Role in disease

In HIV

HIV has been confirmed to target CD4+ T cells and destroy them, making T cell depletion an important hallmark of HIV.[17] In comparison to HIV- individuals, CD4+ T cells proliferate at a higher rate in those who are HIV+. Apoptosis also occurs more frequently in HIV+ patients.[18]

Depletion of regulatory T cells increases immune activation. Glut1 regulation is associated with the activation of CD4+ T cells, thus its expression can be used to track the loss of CD4+ T cells during HIV.[19]

Antiretroviral therapy, the most common treatment for patients with HIV, has been shown to restore CD4+ T cell counts.[20]

The body responds to T cell depletion by producing an equal amount of T cells. However, over time, an individual's immune system can no longer continue to replace CD4+ T cells.[21] This is called the "tap and drain hypothesis."

In cancer

TCD's role in cancer increasing with the rise of immunotherapies being investigated, specifically those that target self-antigens. One example is antigen-specific CD4+ T cell tolerance, which serves as the primary mechanism restricting immunotherapeutic responses to the endogenous self antigen guanylyl cyclase c (GUCY2C) in colorectal cancer.[22] However, in some cases, selective CD4+ T cell tolerance provides a unique therapeutic opportunity to maximize self antigen-targeted immune and antitumor responses without inducing autoimmunity by incorporating self antigen-independent CD4+ T cell epitopes into cancer vaccines.[22]

In a mammary carcinoma model, depletion of CD25+ regulatory T cells increase the amount of CD8+CD11c+PD110, which target and kill the tumors.[23]

In lupus

Phenotypic and functional characteristics of regulatory T cells in lupus patients do not differ from healthy patients. However, depletion of regulatory T cells results in more intense flares of systemic lupus erythematosus. The in vivo depletion of regulatory T cells is hypothesized to occur via early apoptosis induction, which follow exposure to self Ags that arise during the flare.[24]

In murine cytomegalovirus (MCMV) infection

MCMV is a rare herpesvirus that can cause disseminated and fatal disease in the immunodeficient animals similar to the disease caused by human cytomegalovirus in immunodeficient humans. Depletion of CD8+ T cells prior to a MCMV infection effectively upregulates the antiviral activity of natural killer cells. Depletion post infection has no effect on the NK cells.[25]

In arthritis

A preliminary study of the effect on TCD in arthritis in mice models has shown that regulatory T cells play an important role in delayed-type hypersensitivity arthritis (DTHA) inflammation. This occurs by TCD inducing increased neutrofils and activity of IL-17 and RANKL.[26]

Treatment use

Haploidentical stem cell transplantation

TCD is heavily used in haploidentical stem cell transplantation (HSCT), a process in which cancer patients receive an infusion of healthy stem cells from a compatible donor to replenish their blood-forming elements.[27]

In patients with Acute Myeloid Leukemia (AML) and in their first remission, ex vivo TCD greatly reduced the incidence rate of GVHD, though survival was comparable to conventional transplants.[28]

Bone marrow transplantation

In allogeneic bone marrow transplants (BMT), the transplanted stem cells derive from the bone marrow. In cases where the donors are genetically similar, but not identical, risk of GVHD is increased.[29] The first ex vivo TCD trials used monoclonal antibodies, but still had high incidence rates of GVHD. Additional treatment using complement or immunotoxins (along with anti-T-cell antibody) improved the depletion, thus increasing the prevention of GVHD.[30] Depleting αβ T cells from the infused graft spares γδ T cells and NK cells promotes their homeostatic reconstitution, thus reducing the risk of GVHD.[31]

In vitro TCD selectively with an anti-T12 monoclonal antibody lowers the rate of acute and chronic GVHD post allogeneic BMT. Further, immune suppressive medications are usually unnecessary if CD6+ T cells are removed from the donor marrow.[32]

Patients can relapse even after a TCD allogeneic bone marrow transplant, though patients with chronic myelogenous leukemia (CML) who receive a donor lymphocyte infusion (DLI) can restore complete remission.[33]

References

  1. ↑ UPHOFF, DE (March 1958). "Perclusion of secondary phase of irradiation syndrome by inoculation of fetal hematopoietic tissue following lethal total-body x-irradiation.". Journal of the National Cancer Institute 20 (3): 625–32. PMID 13539613. 
  2. ↑ Reisner, Y; Kapoor, N; Kirkpatrick, D; Pollack, MS; Cunningham-Rundles, S; Dupont, B; Hodes, MZ; Good, RA et al. (February 1983). "Transplantation for severe combined immunodeficiency with HLA-A, B, D, DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells.". Blood 61 (2): 341–8. doi:10.1182/blood.V61.2.341.341. PMID 6217853. 
  3. ↑ 3.0 3.1 3.2 Or-Geva, N; Reisner, Y (March 2016). "The evolution of T-cell depletion in haploidentical stem-cell transplantation.". British Journal of Haematology 172 (5): 667–84. doi:10.1111/bjh.13868. PMID 26684279. 
  4. ↑ Daniele, Nicola; Scerpa, Maria; Caniglia, Maurizio; Ciammetti, Chiara; Rossi, Cecilia; Bernardo, Maria; Locatelli, Franco; Isacchi, Giancarlo et al. (2012). "Overview of T-cell depletion in haploidentical stem cell transplantation". Blood Transfusion 10 (3): 264–272. doi:10.2450/2012.0106-11. PMID 22337272. 
  5. ↑ Booth, Claire (2013). "The Current Role of T Cell Depletion in Paediatric Stem Cell Transplantation". British Journal of Haematology 162 (2): 177–190. doi:10.1111/bjh.12400. PMID 23718232. 
  6. ↑ Devine, Steven; Carter, Shelly; Soiffer, Robert; Pasquini, Marcelo; Hari, Parameswaran; Stein, Anthony; Lazarus, Hillard; Linker, Charles et al. (2012). "Low Risk of Chronic Graft Versus Host Disease and Relapse Associated with T-Cell Depleted Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia in First Remission: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303". Biology of Blood and Marrow Transplantation 17 (9): 1343–1351. doi:10.1016/j.bbmt.2011.02.002. PMID 21320619. 
  7. ↑ 7.0 7.1 Antin, Joseph (2011). "T-Cell Depletion in GVHD: Less is More?". Blood 117 (23): 6061–6062. doi:10.1182/blood-2011-04-348409. PMID 21659553. 
  8. ↑ Aversa, F; Bachar-Lustig, E; Or-Geva, N; Prezioso, L; Bonomini, S; Manfra, I; Monti, A; Schifano, C et al. (14 November 2017). "Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide.". Blood Advances 1 (24): 2166–2175. doi:10.1182/bloodadvances.2017009423. PMID 29296864. 
  9. ↑ Marek, A; Stern, M; Ansari, M; Ozsahiri, H; Güngör, T; Gerber, B; Kühne, T; Passweg, JR et al. (2014). "The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT". Bone Marrow Transplantation 49 (1): 55–61. doi:10.1038/bmt.2013.132. PMID 24037023. 
  10. ↑ Lang, P; Schumm, M; Greil, J; Bader, P; Klingebiel, T; Müller, I; Feuchtinger, T; Pfeiffer, M et al. (2005). "A comparison between three graft manipulation methods for haploidentical stem cell transplantation in pediatric patients: preliminary results of a pilot study.". Klinische Padiatrie 217 (6): 334–8. doi:10.1055/s-2005-872529. PMID 16307419. 
  11. ↑ Airoldi, I; Bertaina, A; Prigione, I; Zorzoli, A; Pagliara, D; Cocco, C; Meazza, R; Loiacono, F et al. (9 April 2015). "γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes.". Blood 125 (15): 2349–58. doi:10.1182/blood-2014-09-599423. PMID 25612623. 
  12. ↑ Di Ianni, M; Falzetti, F; Carotti, A; Terenzi, A; Castellino, F; Bonifacio, E; Del Papa, B; Zei, T et al. (7 April 2011). "Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation.". Blood 117 (14): 3921–8. doi:10.1182/blood-2010-10-311894. PMID 21292771. 
  13. ↑ Or-Geva, N; Reisner, Y (August 2014). "Megadose stem cell administration as a route to mixed chimerism.". Current Opinion in Organ Transplantation 19 (4): 334–41. doi:10.1097/MOT.0000000000000095. PMID 24905022. 
  14. ↑ Ophir, E; Or-Geva, N; Gurevich, I; Tal, O; Eidelstein, Y; Shezen, E; Margalit, R; Lask, A et al. (14 February 2013). "Murine anti-third-party central-memory CD8(+) T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells.". Blood 121 (7): 1220–8. doi:10.1182/blood-2012-07-441493. PMID 23223359. 
  15. ↑ Or-Geva, N; Reisner, Y (2015). "Exercising 'veto' power to make haploidentical hematopoietic stem cell transplantation a safe modality for induction of immune tolerance.". Regenerative Medicine 10 (3): 239–42. doi:10.2217/rme.14.94. PMID 25933232. 
  16. ↑ Lask, A; Ophir, E; Or-Geva, N; Cohen-Fredarow, A; Afik, R; Eidelstein, Y; Reich-Zeliger, S; Nathansohn, B et al. (11 April 2013). "A new approach for eradication of residual lymphoma cells by host nonreactive anti-third-party central memory CD8 T cells.". Blood 121 (15): 3033–40. doi:10.1182/blood-2012-06-432443. PMID 23446736. 
  17. ↑ Nishimura, Yoshiaki; Brown, Charles R.; Mattapallil, Joseph J.; Igarashi, Tatsuhiko; Buckler-White, Alicia; Lafont, Bernard A. P.; Hirsch, Vanessa M.; Roederer, Mario et al. (2005-05-31). "Resting naïve CD4+ T cells are massively infected and eliminated by X4-tropic simian–human immunodeficiency viruses in macaques". Proceedings of the National Academy of Sciences of the United States of America 102 (22): 8000–8005. doi:10.1073/pnas.0503233102. ISSN 0027-8424. PMID 15911767. Bibcode: 2005PNAS..102.8000N. 
  18. ↑ Cooper, Arik; García, Mayra; Petrovas, Constantinos; Yamamoto, Takuya; Koup, Richard A.; Nabel, Gary J. (2013-06-20). "HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration". Nature 498 (7454): 376–379. doi:10.1038/nature12274. ISSN 1476-4687. PMID 23739328. Bibcode: 2013Natur.498..376C. https://zenodo.org/record/1233321/files/article.pdf. 
  19. ↑ Palmer, Clovis; Ostrowski, Matias; Gouillou, Maelenn; Tsai, Louis; Yu, Di; Zhou, Jinglin; Henstridge, Darren; Maisa, Anna et al. (2014). "Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection". AIDS 28 (3): 297–309. doi:10.1097/QAD.0000000000000128. PMID 24335483. 
  20. ↑ Nowak, M A; Lloyd, A L; Vasquez, G M; Wiltrout, T A; Wahl, L M; Bischofberger, N; Williams, J; Kinter, A et al. (October 1997). "Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection.". Journal of Virology 71 (10): 7518–7525. doi:10.1128/jvi.71.10.7518-7525.1997. ISSN 0022-538X. PMID 9311831. 
  21. ↑ Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J. M.; Markowitz, M. (1995-01-12). "Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection". Nature 373 (6510): 123–126. doi:10.1038/373123a0. ISSN 0028-0836. PMID 7816094. Bibcode: 1995Natur.373..123H. https://pubmed.ncbi.nlm.nih.gov/7816094/. 
  22. ↑ 22.0 22.1 Snook, Adam; Magee, Michael; Schulz, Stephanie; Waldman, Scott (2014). "Self-tolerance eliminates CD4+ T, but not CD8+ T or B, cells corrupting cancer immunotherapy". European Journal of Immunology 44 (7): 1956–1966. doi:10.1002/eji.201444539. PMID 24771148. 
  23. ↑ Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita; Azogui, Orly (2016). "Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells". PLOS ONE 11 (6): e0157822. doi:10.1371/journal.pone.0157822. PMID 27341421. Bibcode: 2016PLoSO..1157822G. 
  24. ↑ Miyara, Makoto; Amoura, Zahir; Parizot, Christophe; Badoual, Cécile; Dorgham, Karim; Trad, Salim; Nochy, Dominique; Debré, Patrice et al. (2005). "Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus". Journal of Immunology 175 (12): 8392–8400. doi:10.4049/jimmunol.175.12.8392. PMID 16339581. 
  25. ↑ Salem, Mohamad; Hossain, Mohammad (2000). "In vivo acute depletion of CD8+ T cells before murine cytomegalovirus infection upregulated innate antiviral activity of natural killer cells". International Journal of Immunopharmacology 22 (9): 707–718. doi:10.1016/S0192-0561(00)00033-3. PMID 10884591. 
  26. ↑ Atkinson, Sara; Hoffmann, Ute; Hamann, Alf; Bach, Emil; Danneskiold-Samsøe, Niels; Kristiansen, Karsten; Serikawa, Kyle; Fox, Brian et al. (2016). "Depletion of regulatory T cells leads to an exacerbation of delayedtype hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade". Disease Models & Mechanisms 9 (4): 427–440. doi:10.1242/dmm.022905. PMID 26822477. 
  27. ↑ "What is Haploidentical Stem Cell Transplantation?". 2017-01-09. http://blog.dana-farber.org/insight/2017/01/what-is-haploidentical-stem-cell-transplantation/. 
  28. ↑ Ni, Xiong; Song, Qingxiao; Cassady, Kaniel; Deng, Ruishu; Jin, Hua; Zhang, Mingfeng; Dong, Haidong; Forman, Stephen et al. (2017). "PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells". Journal of Clinical Investigation 127 (5): 1960–1977. doi:10.1172/JCI91138. PMID 28414296. 
  29. ↑ "Allogeneic Bone Marrow Transplant". 2021-04-07. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/allogeneic-bone-marrow-transplant. 
  30. ↑ Saad, Ayman; Lamb, Lawrence (2017). "Ex vivo T-cell depletion in allogeneic hematopoietic stem cell transplant: past, present and future". Bone Marrow Transplantation 52 (9): 1241–1248. doi:10.1038/bmt.2017.22. PMID 28319073. 
  31. ↑ Abdelhakim, Haitham; Abdel-Azim, Hisham; Saad, Ayman (2017). "Role of αβ T Cell Depletion in Prevention of Graft versus Host Disease". Biomedicines 5 (3): 35. doi:10.3390/biomedicines5030035. PMID 28672883. 
  32. ↑ Soiffer, RJ (1992). "Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.". Journal of Clinical Oncology 10 (7): 1191–1200. doi:10.1200/JCO.1992.10.7.1191. PMID 1607923. 
  33. ↑ Sehn, Laurie (1999). "Comparative Outcomes of T-Cell–Depleted and Non–T-Cell–Depleted Allogeneic Bone Marrow Transplantation for Chronic Myelogenous Leukemia: Impact of Donor Lymphocyte Infusion". Journal of Clinical Oncology 17 (2): 561–568. doi:10.1200/jco.1999.17.2.561. PMID 10080600. 



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