Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.

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Summary:Donor leukocyte infusion (DLI) has well-documented activity in CML, but the role of DLI in other diseases is less well defined. To evaluate the strategy in multiple myeloma (MM) we evaluated 25 MM patients from 15 centers who were treated with DLI. Patients with persistent or recurrent disease after allogeneic BMT received DLI from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). Chemotherapy was given before DLI in three patients. Two of 22 patients responded completely to DLI alone and three patients responded to the combination of DLI and chemotherapy. Nine patients who had not had sufficient disease control after DLI were given additional DLIs; five of these patients had either complete (two) or partial (three) responses. Thirteen of 25 evaluable patients developed acute GVHD and 11 of 21 evaluable patients developed chronic GVHD; all responders developed GVHD. No patients developed post-DLI pancytopenia. Four patients had responses which lasted Ͼ1 year after DLI, three patients had responses which lasted Ͻ1 year, and three patients had ongoing responses but with followup Ͻ1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders. Graft-versus-host disease (GVHD) occurs in approximately 60% of patients and is closely correlated with disease response. 13 The role of DLI in multiple myeloma (MM) is less certain. Several case reports and small series have documented an apparent graft-versus-myeloma (GVM) effect of DLI, [13][14][15][16][17][18][19][20][21][22][23] and a recent review of the literature 24 suggested an approximately 66% likelihood of response to DLI in myeloma. However, because of the relatively small number of patients reported thus far, and because of the potential for positive reporting bias, the overall usefulness of the approach in MM remains uncertain. To investigate further the role of DLI in MM, we analyzed 25 cases reported from 15 BMT centers. Patients and methods DesignWe collected detailed information from 15 BMT centers about DLIs in 25 patients with MM. Data were collected retrospectively in 13 patients and prospectively in 12. Information collected included the following: demographicspatient sex and age; diagnosis -disease, date of diagnosis, treatment before BMT, and response to treatment; BMTpre-BMT disease status, donor relationship, sex, and degree of histocompatibility, whether the BMT was T cell depleted, occurrence of acute and chronic GVHD; post-BMT relapse -date and extent of relapse, donor chimerism at relapse, and treatment of relapse and response to treatment; DLI -disease extent, pre-DLI chemotherapy and response, date of DLI, total nucleated cell dose, mononuclear cell dose, T cell dose, and concomitant cytokine usage; post-DLI response and complications -response to DLI and date, occurrence of pancytopenia and date, treatment of pancytopenia and res...

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