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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. In humans the first TCD was performed in severe combined immunodeficiency patients.


      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.
      These techniques can be performed either in vivo, ex vivo, or in vitro. 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.
      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. However, complete TCD via ex vivo, especially in acute myeloid leukemia (AML), patients usually does not improve survival. In vivo depletion often uses monoclonal antibodies (eg, alemtuzumab) or heteroantisera. 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. In contrast, both in vivo TCD with alemtuzumab and in vitro TCD with CD34+ selection performed comparably.
      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. 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 and T regulatory cells (Tregs).
      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. 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. These veto cells can also exert graft-versus-tumor effect.


      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. 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.
      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.
      Antiretroviral therapy, the most common treatment for patients with HIV, has been shown to restore CD4+ T cell counts.
      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. 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. 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.
      In a mammary carcinoma model, depletion of CD25+ regulatory T cells increase the amount of CD8+CD11c+PD110, which target and kill the tumors.


      = 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.


      = 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.


      = 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.


      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.
      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.


      = 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. 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. 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.
      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.
      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.


      References

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    T-Cell Depletion Therapy | Semantic Scholar

    T-Cell Depletion Therapy | Semantic Scholar

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    t cell depletion

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    T-cell depletion - Wikipedia

    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.

    In vivo depletion of CD4- and CD8-specific T cells - PubMed

    Depletion of the appropriate subset of T cells is verified by flow cytometry analysis of lymph node and spleen cell suspensions in pilot experiments. Once conditions have been established, depleted mice can be used to study the impact of T cell subsets on in vivo immune responses.

    Mechanisms of T-cell Depletion in Tumors and Advances in …

    T-cell depletion is a state of diminished function characterized by the progressive loss of T-cell effector function and self-renewal ability. It is considered a major resistance mechanism to tumor cell immunotherapy.

    Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 …

    In order to understand the correlation between CD4+ T-cell depletion and immunopathogenesis, and its relationship with disease progression, a number of dynamic models have been put forward. Two of the most acknowledged mechanisms are discussed in detail in this review.

    Removing Naive T Cells May Prevent Chronic GVHD - NCI

    Feb 17, 2022 · Targeted T-cell depletion: Getting rid of naive T cells only. Researchers had previously tried removing all T cells from donated cells before transplantation, a strategy called T cell depletion. But not all T cells are created equal.

    Selective depletion of naïve T cells by targeting CD45RA

    Early approaches to ex vivo T-cell depletion involved pan–T-cell depletion techniques such as negative depletion of CD3 + T cells or positive selection of CD34 + cells, both of which lead to profound depletion of all donor T-cell subsets.

    Antigen-specific depletion of CD4+ T cells by CAR T cells reveals ...

    Oct 7, 2022 · In a mouse experimental autoimmune encephalomyelitis model of MS-like disease, deletion of higher-affinity T cells was sufficient to prevent disease onset, whereas targeting lower-affinity T cells was necessary to reverse ongoing disease. These findings highlight strategies for designing CAR T cells to target distinct stages of autoimmune disease.

    T Cell Depletion - an overview | ScienceDirect Topics

    Global T-cell depletion is used to dampen T-cell responses in autoimmune disorders and as induction therapy in transplant recipients at risk for early acute rejection. Commonly used T-cell depleting agents include anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) containing antibodies directed at multiple specificities such as ...

    Architects of immunity: How dendritic cells shape CD8+ T cell

    Jan 17, 2025 · Activation of CD8 + T cells is essential for productive anticancer immunity. This process involves steps outlined in the cancer-immunity cycle (1), starting with the capture, processing, and presentation of tumor-derived antigens by dendritic cells (DCs).

    Restimulation by macrophages exhausts T cells - ScienceDirect

    Jan 14, 2025 · Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. ... In contrast, depletion of dendritic cells by using a mouse model bearing diphteria toxin receptor in CD11c + cells or depletion of microglia by CSF1R inhibition had no effect on the differentiation trajectory of exhausted T cells.