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Graft-versus-host disease: a surge of developments.

Riddell SR, Appelbaum FR - PLoS Med. (2007)

View Article: PubMed Central - PubMed

Affiliation: Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington, United States of America.

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This year approximately 20,000 individuals will receive an allogeneic hematopoietic cell transplant (HCT) as treatment for a malignant, or life-threatening non-malignant, hematopoietic disease... The process of HCT generally begins with administration of a preparative regimen to eradicate the underlying disease and immunosuppress the patient in order to prevent rejection of the subsequently transfused hematopoietic stem cells... If no immunosuppression is given after allogeneic HCT, life-threatening or fatal GVHD inevitably develops... The majority of patients eventually develop tolerance, and immunosuppression can be completely withdrawn in these cases, but 10%–20% of recipients of HLA-matched hematopoietic cell transplants will die of refractory GVHD or of opportunistic infections associated with its prevention or treatment, and the mortality rate increases with increasing donor–recipient HLA disparity... Increased graft rejection may also occur if donor T cells are removed from the donor stem cell graft, because the reaction of these cells against residual host immune cells contributes to engraftment... More intensive preparative regimens can overcome this problem but are associated with increased toxicity... Using a novel technique that allows for the typing of individual DNA strands, Petersdorf et al. have now shown that among allele-matched unrelated donor–recipient pairs, those that shared the same physical linkage of HLA-A, -B, and -DRB1 were much less likely to develop severe GVHD (Figure 2)... These results imply that other unidentified transplantation antigens exist within the same genetic region as HLA, and offer a method for improved selection among HLA-matched unrelated donors... The pathogenesis of GVHD involves the expansion and differentiation of donor T cells reacting in peripheral lymphoid tissues against host antigen-presenting cells that display disparate minor histocompatibility antigens... These antigen-presenting cells are activated as a consequence of tissue injury and the resulting release of proinflammatory cytokines... Although these new approaches to allogeneic HCT are likely to reduce the severity of GVHD, an important concern for patients undergoing HCT for a malignant disease is whether reducing GVHD might increase the risk of tumor recurrence... Pilot studies in which cloned donor T cells reactive with minor histocompatibility antigens have been adoptively transferred to treat patients with post-transplant disease recurrence have demonstrated the principle that GVT and GVHD can be segregated based on the tissue expression of the target antigen... The feasibility of this strategy is advancing with refinements in the culture methods used for isolating effector T cells from naïve T cell precursors and programming these effector cells for GVT activity... Thus, strategies to abrogate GVHD and its complications need not be associated with loss of the GVT effect, but may instead employ targeted immunotherapy to reduce the intensity and duration of post-grafting immunosuppression while augmenting GVT activity... The human graft-versus-host reaction continues to both fascinate and frustrate clinical investigation with its lack of predictability, possibly lethal toxicity, but potentially lifesaving anti-tumor effects.

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Clinical Appearance of Acute Graft-Versus-Host Disease Involving the Skin and the Upper Intestinal MucosaLeft panel: The diffuse erythematous maculopapular rash typical of acute GVHD. Right panel: an endoscopic view of the edematous, reddened, friable gastrointestinal mucosa seen in a patient with acute GVHD.
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pmed-0040198.g001: Clinical Appearance of Acute Graft-Versus-Host Disease Involving the Skin and the Upper Intestinal MucosaLeft panel: The diffuse erythematous maculopapular rash typical of acute GVHD. Right panel: an endoscopic view of the edematous, reddened, friable gastrointestinal mucosa seen in a patient with acute GVHD.

Mentions: This year approximately 20,000 individuals will receive an allogeneic hematopoietic cell transplant (HCT) as treatment for a malignant, or life-threatening non-malignant, hematopoietic disease. The process of HCT generally begins with administration of a preparative regimen to eradicate the underlying disease and immunosuppress the patient in order to prevent rejection of the subsequently transfused hematopoietic stem cells. Following HCT, donor T cells transplanted with or developing from the hematopoietic stem cells react with cells of the human leukocyte antigen (HLA)-matched but genetically non-identical host, providing a beneficial graft-versus-tumor (GVT) response but also resulting in possibly life-threatening graft-versus-host disease (GVHD). The manifestations of GVHD vary over its course. Acute GVHD usually appears within several weeks of HCT and is characterized by a diffuse maculopapular rash, mucosal inflammation causing crampy abdominal pain and diarrhea, and elevated liver function tests (Figure 1). GVHD that first appears or persists more than three months after allogeneic HCT is termed chronic GVHD and resembles a chronic autoimmune disorder. Patients frequently develop lichen planus skin lesions, ocular and oral sicca, obliterative bronchiolitis, and hepatic abnormalities resembling primary biliary sclerosis.


Graft-versus-host disease: a surge of developments.

Riddell SR, Appelbaum FR - PLoS Med. (2007)

Clinical Appearance of Acute Graft-Versus-Host Disease Involving the Skin and the Upper Intestinal MucosaLeft panel: The diffuse erythematous maculopapular rash typical of acute GVHD. Right panel: an endoscopic view of the edematous, reddened, friable gastrointestinal mucosa seen in a patient with acute GVHD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1913094&req=5

pmed-0040198.g001: Clinical Appearance of Acute Graft-Versus-Host Disease Involving the Skin and the Upper Intestinal MucosaLeft panel: The diffuse erythematous maculopapular rash typical of acute GVHD. Right panel: an endoscopic view of the edematous, reddened, friable gastrointestinal mucosa seen in a patient with acute GVHD.
Mentions: This year approximately 20,000 individuals will receive an allogeneic hematopoietic cell transplant (HCT) as treatment for a malignant, or life-threatening non-malignant, hematopoietic disease. The process of HCT generally begins with administration of a preparative regimen to eradicate the underlying disease and immunosuppress the patient in order to prevent rejection of the subsequently transfused hematopoietic stem cells. Following HCT, donor T cells transplanted with or developing from the hematopoietic stem cells react with cells of the human leukocyte antigen (HLA)-matched but genetically non-identical host, providing a beneficial graft-versus-tumor (GVT) response but also resulting in possibly life-threatening graft-versus-host disease (GVHD). The manifestations of GVHD vary over its course. Acute GVHD usually appears within several weeks of HCT and is characterized by a diffuse maculopapular rash, mucosal inflammation causing crampy abdominal pain and diarrhea, and elevated liver function tests (Figure 1). GVHD that first appears or persists more than three months after allogeneic HCT is termed chronic GVHD and resembles a chronic autoimmune disorder. Patients frequently develop lichen planus skin lesions, ocular and oral sicca, obliterative bronchiolitis, and hepatic abnormalities resembling primary biliary sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

This year approximately 20,000 individuals will receive an allogeneic hematopoietic cell transplant (HCT) as treatment for a malignant, or life-threatening non-malignant, hematopoietic disease... The process of HCT generally begins with administration of a preparative regimen to eradicate the underlying disease and immunosuppress the patient in order to prevent rejection of the subsequently transfused hematopoietic stem cells... If no immunosuppression is given after allogeneic HCT, life-threatening or fatal GVHD inevitably develops... The majority of patients eventually develop tolerance, and immunosuppression can be completely withdrawn in these cases, but 10%–20% of recipients of HLA-matched hematopoietic cell transplants will die of refractory GVHD or of opportunistic infections associated with its prevention or treatment, and the mortality rate increases with increasing donor–recipient HLA disparity... Increased graft rejection may also occur if donor T cells are removed from the donor stem cell graft, because the reaction of these cells against residual host immune cells contributes to engraftment... More intensive preparative regimens can overcome this problem but are associated with increased toxicity... Using a novel technique that allows for the typing of individual DNA strands, Petersdorf et al. have now shown that among allele-matched unrelated donor–recipient pairs, those that shared the same physical linkage of HLA-A, -B, and -DRB1 were much less likely to develop severe GVHD (Figure 2)... These results imply that other unidentified transplantation antigens exist within the same genetic region as HLA, and offer a method for improved selection among HLA-matched unrelated donors... The pathogenesis of GVHD involves the expansion and differentiation of donor T cells reacting in peripheral lymphoid tissues against host antigen-presenting cells that display disparate minor histocompatibility antigens... These antigen-presenting cells are activated as a consequence of tissue injury and the resulting release of proinflammatory cytokines... Although these new approaches to allogeneic HCT are likely to reduce the severity of GVHD, an important concern for patients undergoing HCT for a malignant disease is whether reducing GVHD might increase the risk of tumor recurrence... Pilot studies in which cloned donor T cells reactive with minor histocompatibility antigens have been adoptively transferred to treat patients with post-transplant disease recurrence have demonstrated the principle that GVT and GVHD can be segregated based on the tissue expression of the target antigen... The feasibility of this strategy is advancing with refinements in the culture methods used for isolating effector T cells from naïve T cell precursors and programming these effector cells for GVT activity... Thus, strategies to abrogate GVHD and its complications need not be associated with loss of the GVT effect, but may instead employ targeted immunotherapy to reduce the intensity and duration of post-grafting immunosuppression while augmenting GVT activity... The human graft-versus-host reaction continues to both fascinate and frustrate clinical investigation with its lack of predictability, possibly lethal toxicity, but potentially lifesaving anti-tumor effects.

Show MeSH
Related in: MedlinePlus