T-cell depletion

T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its response. 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. T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its response. 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. 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 c ytomegalovirus (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 vs tumor effect. CD4+ T cell depletion is one of two hallmarks of HIV. Depletion of regulatory T cells increase immune activation, the second hallmark of HIV. Glut1 regulation is associated with the activation of CD4+ T cells, thus its expression can be used track the loss of CD4+ T cells during HIV. In comparison to HIV- individuals, CD4+ T cells proliferate at a higher rate in HIV+, which is modulated by type I interferons. 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.