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CTL directed against minor histocompatibility Ags (mHag) play a major role in antileukemia reactivity after HLA-identical bone marrow transplantation. Some of these mHag are restricted to hemopoietic cells, others show a broad tissue expression. Therefore, antileukemia reactivity is often associated with graft-vs-host disease. Here, we report the identification of a B cell leukemia-associated mHag, HB-1, recognized by a CD8+ CTL clone derived from peripheral blood of an acute lymphoblastic B cell leukemia patient who has been treated by HLA-matched bone marrow transplantation. Interestingly, the CTL clone that recognizes HB-1 exhibits specific cytotoxicity toward leukemic as well as EBV-transformed B cells, but not against untransformed B cells. Moreover, the CTL clone does not lyse PHA-stimulated T cell blasts, monocytes, and fibroblasts, indicating that HB-1 is mainly expressed by transformed B cells. Further analysis reveals that HB-1 is restricted by HLA-B44 (both B*4402 and B*4403) and that 28% of HLA-B44-positive individuals express HB-1. These findings demonstrate that leukemia-associated mHag with a restricted tissue distribution, such as HB-1, elicit CTL reactivity in vivo. These Ags are of potential use in immunotherapy against leukemia because they generate antileukemia reactivity that is not associated with graft-vs-host disease.

Contains fulltext : 50855.pdf (Publisher’s version ) (Open Access) Severe combined immunodeficiencies (SCID) are commonly fatal early in life. Adequate diagnosis and rapid institution of treatment, such as allogeneic stem cell transplantation (SCT), is essential. Several studies demonstrated that reconstitution of B-cell function after SCT is better in B-positive SCID than in B-negative SCID. We demonstrate that B-cell reconstitution in a B-negative SCID patient due to an Artemis mutation required the elimination of the autologous precursor-B-cells in bone marrow, probably to create physical space in the precursor-B-cell niches. Apparently, occupation of the precursor-B-cell niches is a potential dominant factor influencing repopulation of a functional B-cell compartment in B-negative SCID.

This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10(-8 )mol/L (about 1.8 microg/mL). Because most natural killer (NK) cells are CD7(+), NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m(2) IT combination, administered intravenously at 48-hour intervals. The T(1/2) was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells. (Blood. 2000;95:3693-3701)

Contains fulltext : 27126___.PDF (Publisher’s version ) (Open Access)