Graft-versus-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation for hematologic diseases. Antigen mismatches due to polymorphic differences between the patient and ...donor are central in the mechanisms of GVHD. Polymorphisms are known for FcγRIIa, and this molecule is present on endothelial, dendritic, and Langerhans cells. Donor cells reacting against the patient as GVHD can also react against the malignancy of the patient, and this is known as the graft-versus-leukemia (GVL) effect. Because the FcγRIIa molecule is also present on acute myeloid leukemia (AML) cells, an FcγRIIa mismatch could be a target for both GVHD and GVL. We retrospectively studied 73 AML patients and analyzed the differences in GVHD and relapse incidence between patients with and without a pro-GVHD/GVL FcγRIIa allotype mismatch. We observed a difference in FcγRIIa receptors with a pro-GVHD/GVL mismatch in 18 patient/donor pairs (25%). Univariate and multivariate analyses demonstrated the pro-GVHD mismatch to be a significant risk factor for the development of acute GVHD. There was no effect on the occurrence of chronic GVHD. The relapse incidence was not significantly different for patients with or without the pro-GVL mismatch, although there was a trend for fewer relapses in standard-risk AML patients with the pro-GVL mismatch. We conclude that the polymorphism of the FcγRIIa receptor may be a candidate target for acute GVHD.
Graft-versus-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation for hematologic diseases. Antigen mismatches due to polymorphic differences between the patient and ...donor are central in the mechanisms of GVHD. Polymorphisms are known for FcgammaRIIa, and this molecule is present on endothelial, dendritic, and Langerhans cells. Donor cells reacting against the patient as GVHD can also react against the malignancy of the patient, and this is known as the graft-versus-leukemia (GVL) effect. Because the FcgammaRIIa molecule is also present on acute myeloid leukemia (AML) cells, an FcgammaRIIa mismatch could be a target for both GVHD and GVL. We retrospectively studied 73 AML patients and analyzed the differences in GVHD and relapse incidence between patients with and without a pro-GVHD/GVL FcgammaRIIa allotype mismatch. We observed a difference in FcgammaRIIa receptors with a pro-GVHD/GVL mismatch in 18 patient/donor pairs (25%). Univariate and multivariate analyses demonstrated the pro-GVHD mismatch to be a significant risk factor for the development of acute GVHD. There was no effect on the occurrence of chronic GVHD. The relapse incidence was not significantly different for patients with or without the pro-GVL mismatch, although there was a trend for fewer relapses in standard-risk AML patients with the pro-GVL mismatch. We conclude that the polymorphism of the FcgammaRIIa receptor may be a candidate target for acute GVHD.
Objective
Fc receptors for IgG (FcγR) play a prominent role in the clearance of immune complexes in systemic lupus erythematosus (SLE). Polymorphisms of FcγR have been proposed as genetic factors ...that influence susceptibility to SLE. We analyzed 3 functional FcγR polymorphisms in a strictly Caucasian population of SLE patients, and determined the influence of these polymorphisms on the clearance of immune complexes in vivo.
Methods
Genomic DNA was isolated from 230 Caucasian patients with SLE and 154 controls. Amplification of FcγR‐genomic regions in allotype‐specific polymerase chain reactions was used to distinguish the genotypes. In addition, we analyzed the FcγR genotypes of 13 patients with SLE who participated in a study determining the half‐life of IgG‐coated erythrocytes in the blood.
Results
We found a strong trend toward skewing of FcγRIIa, with an enrichment of the homozygous FcγRIIa‐R/R131 genotype in patients compared with controls. We did not find a correlation between this genotype and the development of lupus nephritis. However, we established that the half‐life of IgG‐coated erythrocytes in the blood was prolonged in patients expressing the FcγRIIa‐R/R131 genotype. The homozygous FcγRIIIa‐F/F158 genotype was found more frequently in patients with arthritis and/or serositis.
Conclusion
In Caucasian populations, the R/H polymorphism of FcγRIIa is a minor determinant in susceptibility to SLE, whereas the V/F polymorphism of FcγRIIIa is associated with a set of disease manifestations. Notably, the R/H polymorphism of FcγRIIa affects the clearance of immune complexes in vivo, which may influence the course of a disease such as SLE.
Summary
Thrombin-induced changes in cytosolic free Ca
2+
(Ca
2+
i
) were studied in human platelets that had been stored for up to 6 days. Changes in Ca
2+
i
were measured with Indo-1-loaded ...platelets and quantitated with two different methods: (i) measurement of the changes in total fluorescence; (ii) measurement of the Ca
2+
i
changes in individual platelets in a flow cytometer, allowing the detection of non-responding platelets. The maximal concentration of Ca
2+
i
after stimulation with 0.5 U of thrombin/ml decreased from 544 ± 58 nM (mean ± SEM, n = 6) on day 0, to 276 ± 9 nM on day 3 and to 203 ± 23 nM on day 6. The percentage of platelets responding to 0.5 U of thrombin/ml declined from 90 ± 2% on day 0 to 72 ± 4% on day 3, and to 47 ± 8% on day 6. Nevertheless, also the responding platelets showed a decreased rise in Ca
2+
i
.
The study shows that during platelet storage a decrease in the rise in Ca
2+
i
upon thrombin stimulation occurs. This decrease is partly due to the formation of a subpopulation of platelets that is completely unresponsive and partly due to a decreased responsiveness in the remainder of the platelets; it is not due to a gradual decline in Ca
2+
i
rise in all platelets. This phenomenon provides new insight in the functional defect of stored platelets.
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