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We retrospectively analyzed the development of lymphocytes and of the main immunological functions in 33 patients with severe combined immunodeficiency who survived at least 6 months after bone marrow transplantation (BMT). Eighteen patients received HLA-identical BM and 15 received HLA-nonidentical BM. Development of immune functions occurred faster after HLA-identical BMT as full T- and B-lymphocyte- mediated responses were present at day 186 versus 505, respectively (P = .05). In addition, antibody responses remain completely or partially absent in 8 of 15 patients of the second group. Detection of antibody response after HLA-incompatible BMT correlated with engraftment of donor B cells in informative cases. In patients who received an HLA- nonidentical BMT after chemotherapy (6 of 15), development of immune functions occurred more rapidly and 6 of 6 had B-cell functions, including normal antibody production. Autoimmunity was not uncommon and was found after HLA-incompatible BMT (4 of 15) or after HLA-partially phenotypically identical BMT (2 of 3). Antibodies were in most cases specific for blood cells. Occurrence of autoimmunity correlates with poor B-cell functions and to a lesser extent with defective T-cell responses. This type of study may lead to definition of a more accurate strategy for performing BMT in patients with severe combined immunodeficiency.

Specific and recurrent chromosomal rearrangements are often observed in the karyotypes of phytohemagglutinin-stimulated lymphocytes. The percentage of cells demonstrating these rearrangements is dramatically increased in the genetic disease ataxia telangiectasia. Inversion of chromosome 7 represents approximately half of the chromosomal rearrangements in this disease. Because the chromosomal locations of the inv(7) breakpoints coincide precisely with those of the T-cell antigen receptor (TCR) beta and gamma genes, it has been hypothesized that this rearrangement may occur by recombination between those two loci. Here, we present direct evidence that inversion of chromosome 7 in ataxia telangiectasia is generated by site-specific recombination between a TCR gamma variable segment and a TCR beta joining segment.

Three consecutive patients with the severe phenotype of leukocyte adhesion deficiency characterized by a defective expression of LFA-1, Mac-1 (CR3), and p150.95 on leukocytes have received HLA partially incompatible bone marrow transplantation (BMT). The degree of HLA incompatibility between related donors and recipients was 2 HLA antigens in one and one full haplotype in the two others. Graft-v-host disease (GVHD) prophylaxis consisted in T-cell depletion of the bone marrow inoculum and a 60-day course of cyclosporin A. A first attempt led to autologous recovery in one patient. The second transplant in this patient and the first transplant in the two others led to stable partial engraftment of lymphocytes and phagocytic cells, as shown by expression of adhesion molecules (LFA-1, Mac-1) on leukocytes and by HLA typing and restriction fragment-length polymorphism studies using minisatellite probes. Although the level of mixed chimerism was lower in one patient (7% to 30% donor cells) and greater than 50% in the two others, recovery of lymphocyte and phagocytic cell functions was sufficient enough to allow the patient to lead a normal life, infection free in the three cases. These patients, now 57, 32, and 19 months post- transplant, are in good condition without any therapy. These results lead us to propose that the LFA-1 molecule plays a role in HLA- incompatible graft rejection, probably by mediating adhesion of cytotoxic T and non-T lymphocytes to their targets.

We have studied the coagulation status of eight patients with the Chediak-Higashi syndrome (CHS), both in the chronic and the accelerated phase of the disease. It has been shown that during the accelerated phase there are coagulation abnormalities. These abnormalities include a peripheral thrombocytopenia, minor alterations of liver clotting factors, and mainly a profound hypofibrinogenemia and hypoplasminogenemia, which cause life-threatening bleedings. These disorders are of complex origin, but a fibrinolytic process, possibly primary, appears to play a significant role, since the present evidence for intravascular coagulation is not definitive. The accelerated phase of the CHS is characterized by a visceral infiltration by macrophages and lymphocytes. Therefore, we have investigated the possible role of the macrophages in the fibrinolytic process. We have found an excessive plasminogen activator (PA) production by CHS mononuclear cells in the accelerated phase and to a lesser extent in the chronic phase, except in one patient in whom no anomaly was found. Single-cell studies revealed an increased number of PA-producing cells among the monocyte- macrophage lineage rather than a higher level of production per cell. Polymorphonuclear cells (PMN) from patients with CHS were also shown to contain more PA. Slight but significant abnormalities in PA production were observed in obligatory heterozygotes (five out of nine), indicating the inherited nature of the excessive PA production. Finally, an enhanced PA production was similarly demonstrated using beige mice macrophages. The exacerbated production of PA by macrophages in the accelerated phase of the CHS can account to some extent for the coagulation abnormalities that have been observed.

We have studied the coagulation status of eight patients with the Chediak-Higashi syndrome (CHS), both in the chronic and the accelerated phase of the disease. It has been shown that during the accelerated phase there are coagulation abnormalities. These abnormalities include a peripheral thrombocytopenia, minor alterations of liver clotting factors, and mainly a profound hypofibrinogenemia and hypoplasminogenemia, which cause life-threatening bleedings. These disorders are of complex origin, but a fibrinolytic process, possibly primary, appears to play a significant role, since the present evidence for intravascular coagulation is not definitive. The accelerated phase of the CHS is characterized by a visceral infiltration by macrophages and lymphocytes. Therefore, we have investigated the possible role of the macrophages in the fibrinolytic process. We have found an excessive plasminogen activator (PA) production by CHS mononuclear cells in the accelerated phase and to a lesser extent in the chronic phase, except in one patient in whom no anomaly was found. Single-cell studies revealed an increased number of PA-producing cells among the monocyte-macrophage lineage rather than a higher level of production per cell. Polymorphonuclear cells (PMN) from patients with CHS were also shown to contain more PA. Slight but significant abnormalities in PA production were observed in obligatory heterozygotes (five out of nine), indicating the inherited nature of the excessive PA production. Finally, an enhanced PA production was similarly demonstrated using beige mice macrophages. The exacerbated production of PA by macrophages in the accelerated phase of the CHS can account to some extent for the coagulation abnormalities that have been observed.

Cytogenetically abnormal T-cell nonmalignant clones are a characteristic feature of ataxia telangiectasia (AT). Here, we study a t(14;14) clone from a patient with AT, and provide a cytological, immunological, and molecular characterization. This cellular population is clonal at the molecular level, but is phenotypically heterogeneous, with CD4+CD8+ and CD4-CD8+ cells. Although these cells do not divide in the peripheral blood, a majority of them are found in G1 phase and express the membrane antigen 4F2, a very early marker of activation. Many similarities are found between this nonmalignant AT clone and T- cell prolymphocytic leukemia at the morphologic, cytogenetic, and immunologic levels, despite the different clinical courses associated with these proliferations. We hypothesize that the t(14;14) translocation is linked to the abnormal morphology and immunophenotype of the AT clone cells, but that this translocation confers only a preactivated state to the cells. A complete malignant transformation would then be due to secondary events.

Eight patients with severe combined immunodeficiency received bone marrow cells from their HLA haplotype-identical fathers after bone marrow T cell depletion by rosetting with neuraminidase-treated sheep red cells. Because the method led to the infusion of a small percentage of T lymphocytes (0.1% to 0.3%), cyclosporin was given by continuous intravenous infusion for two months in order to prevent the occurrence of graft-v-host disease (GVHD). Three patients who did have residual nonfunctional T lymphocytes received busulfan and cyclophosphamide before transplantation. Engraftment was observed in seven patients, and severe GVHD was not seen. Two patients died early after the bone marrow transplantation because of prior infections, and a third died at day 90 from a B cell lymphoproliferative syndrome. The five other patients are doing well. Stable engraftment has been achieved with reconstitution of cell-mediated immunity in 5/5 and humoral immunity in 4/5 patients.