11Are there effective new strategies for the treatment of acute and chronic GvHD?
Introduction
The best new strategy for treatment of both acute and chronic graft-versus-host disease (GvHD) is prevention. It has been known for years that T cells are the cause of GvHD in the acute setting. Eliminate T cells and there is no GvHD. However, without T cells, the risk of relapse is high; but where T cell populations are high, the risk of GvHD is high. Clinically, the goal is to maintain enough T cells to establish a good anti-leukemia effect, but not enough to cause GvHD. To do that, an understanding of the process of T-cell production and maturation is required. T cells can be approached in various ways: as CD4 and CD8 cells; as TH1, TH2, Tc1, and Tc2 cells; as naïve, memory, central memory, and effector memory cells; and as inflammatory, regulatory, or veto cells. Understanding what each subset of these cells represents in normal immune processes is basic to the goal of balancing the need for graft-versus-leukemia effect with the risk of GvHD.
Section snippets
Development of normal T cells
The major morbidity of GvHD may arise from the fact that the immune system in a patient who has undergone bone marrow transplant is not normal. A normal immune system requires a normal marrow as the source of precursors and functioning secondary lymphoid organs including the thymus. These support both innate (neutrophils, monocytes, dendritic cells, and natural killer (NK) cells) and adaptive (T cells, B cells, and dendritic cells) immunity. Precursors from the marrow travel to the thymus and
Development of restricted T cells
When the normal peripheral T-cell pool is damaged by cancer chemotherapy, transplantation, infection, or stress, it must be reconstituted with naïve cells. However, for the T-cell population to return to normal, a functional thymus must be present. The functional status of the thymus is determined by age and how much damage was sustained during therapy, and dictates the quantity and quality of T-cell reconstitution. T-cell reconstitution in older adults and individuals with atrophied thymuses
Reconstituting the immune system after transplantation: the key to avoiding acute GvHD?
As described above, a degree of progressive thymic atrophy is normal with age. The thymic epithelial space decreases; the perivascular space expands with the dipocytes; the overall thymic output of naïve cells significantly drops. Thymopoiesis persists up to at least the eighth decade of life, but the available functional tissue shrinks and is very susceptible to damage by chemotherapy or radiation. Reconstituting the immune response following transplantation improves outcome. It is also a
Chronic GvHD
The incidence of chronic GvHD appears to be increasing with the rising number of grafts overall, but particularly in older patients. Pavletic and colleagues at the NIH have focused on gaining consensus about approaches to chronic GvHD8, but the etiology and optimal therapy for GvHD remain elusive.
One interesting line of research in GvHD explores the role of the B-cell activating factor, BAFF/BLyS. This is part of the tumor necrosis factor (TNF) family and is a key regulator of B-cell
Conclusion
There is still an enormous amount that is not known about the molecular biology underlying GvHD, but exploration of the development and derangement of both the innate and adaptive immune systems is beginning to provide interesting details of relevant pathways and polymorphisms. Recent work in gene expression profiling suggests a critical next step in identifying broader patterns that will stand up to examination in independent data sets and provide a sturdy basis for targeted therapy and
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2016, Pharmacological ResearchCitation Excerpt :GVHD is caused by donor T cells that recognize and react to alloantigens of the recipient [70]. Upon APC activation, donor T cells become alloreactive effector T cells producing high levels of inflammatory cytokines (e.g., TNF-α, IFN-γ, IL-4 and IL-17) and cytotoxic molecules, leading to host tissue injury and the subsequent life-threatening complication [47,69,88–93]. However, blockade of individual effector molecules has limited efficacy in controlling GVHD [69,93].
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