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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 The majority of patients eventually develop tolerance, and immunosuppression can be completely withdrawn in these cases, but 10%–20% of recipients of HLA-matched hematopoietic cell transplants will die of refractory GVHD or of opportunistic infections associated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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Schematic Illustration of the HLA Haplotypes of a Patient and 4 HLA Phenotypically Identical Potential DonorsData suggest that the use of the single haplotype-matched donor reduces acute graft-versus-host disease.
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pmed-0040198.g002: Schematic Illustration of the HLA Haplotypes of a Patient and 4 HLA Phenotypically Identical Potential DonorsData suggest that the use of the single haplotype-matched donor reduces acute graft-versus-host disease.

Mentions: One area of progress, as noted above, has been in HLA-typing technology and donor selection. Historically, HLA typing was conducted using serologic methods, but with the advent of the polymerase chain reaction assay in the 1980s, it became possible to perform molecular typing of donor and recipient. When patients previously transplanted from serologically matched donors were retrospectively analyzed using molecular typing, approximately 30% were found to be mismatched with the donor for one or more alleles, and such mismatching was shown to lead to more GVHD and poorer survival [5]. Thus, molecular typing of the HLA locus has become the standard of care. Even with the use of molecular typing to identify fully HLA-matched donors, unrelated donor transplants continue to be associated with more GVHD than seen with HLA-matched sibling transplants. 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) [6]. 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.


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

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

Schematic Illustration of the HLA Haplotypes of a Patient and 4 HLA Phenotypically Identical Potential DonorsData suggest that the use of the single haplotype-matched donor reduces acute graft-versus-host disease.
© Copyright Policy
Related In: Results  -  Collection

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

pmed-0040198.g002: Schematic Illustration of the HLA Haplotypes of a Patient and 4 HLA Phenotypically Identical Potential DonorsData suggest that the use of the single haplotype-matched donor reduces acute graft-versus-host disease.
Mentions: One area of progress, as noted above, has been in HLA-typing technology and donor selection. Historically, HLA typing was conducted using serologic methods, but with the advent of the polymerase chain reaction assay in the 1980s, it became possible to perform molecular typing of donor and recipient. When patients previously transplanted from serologically matched donors were retrospectively analyzed using molecular typing, approximately 30% were found to be mismatched with the donor for one or more alleles, and such mismatching was shown to lead to more GVHD and poorer survival [5]. Thus, molecular typing of the HLA locus has become the standard of care. Even with the use of molecular typing to identify fully HLA-matched donors, unrelated donor transplants continue to be associated with more GVHD than seen with HLA-matched sibling transplants. 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) [6]. 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.

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