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]
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 can be effective in preventing GvHD, there are several potential problematic side-effects such as a delay in recovery of the immune system of the transplanted individual or a decreased graft-versus-tumor effect. This problem is partially answered by more selective depletion, such as depletion of CD3+ or TCRα/β+ T-cells and CD19+ B cells, 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 can prevent rejection because the stem cells have the ability to protect themselves from the host's immune system (i.e. veto cell killing).[13] Experiments show that transplantation of other types of veto cells along with megadose haploidentical HSCT reduces 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-versus-tumor effect.[16]