Alan Winkelstein

Relationship of CD34+ cell dose to early and late hematopoiesis following autologous peripheral blood stem cell transplantation

We evaluated early and late hematopoietic reconstitution in 27 patients with advanced lymphoma, Hodgkin’s disease, and breast or ovarian cancer after treatment using high-dose/myeloablative conditioning regimens and autologous peripheral blood stem cell (PBSC) transplantation. Eighteen patients (67%) received G-CSF 5 μ g/kg/day following chemotherapy and nine (33%) were mobilized using G-CSF alone. Each patient had 7 × 108 mononuclear cells (MNC) per kg collected. G-CSF was administered post-PBSC infusion. While all patients showed prompt granulocyte recovery by day 14, platelet recovery failed to occur in four (15%) heavily pretreated patients with non-Hodgkin’s lymphoma. Retrospective analysis in 17 patients revealed that the infused number of CD34 surface antigen-positive cells correlated with time to granulocyte (r = 0.59, P = 0.012) and platelet (r = 0.58, P = 0.021) recovery. Patients receiving the higher numbers of CD34+ cells had consistently better hematologic parameters at all times examined. At 180 days post-transplant, the median Hb level was 124 g/l vs 88 g/l (P = 0.004); platelet count was 202 × 109/l vs 25 × 109/l (P = 0.004); and neutrophil count was 3100 × 106/l vs 1400 × 106/l (P = 0.15). Hemoglobin strongly correlated with the CD34+ cell dose at 360 days (r = 0.90, P = 0.01). We conclude that graft CD34+ cell content appears to be an indicator of the quality of late as well as early hematopoietic function.

Fasting-enhanced immune effector mechanisms in obese subjects

Acute nutritional deprivation occurs frequently in clinical practice, yet little data exist on its effect on immune host defenses. To investigate this question, various immune parameters were studied in 15 obese subjects before and after a 14-day fast. Blood monocyte bactericidal activity and natural killer cell cytolytic activity were enhanced by fasting: monocyte killing increased in 12 of 14 subjects (p less than 0.05) and natural killer cell activity increased an average of 24 percent in 13 subjects tested (p less than 0.02). Starvation also enhanced parameters of humoral immunity as evidenced by increases in serum concentrations of IgG, IgA, and IgM (p less than 0.01). By contrast, lymphocyte blastogenic responses to the mitogen phytohemagglutinin were modestly decreased. Peripheral blood leukocyte counts, including neutrophils, T cells, and B cells, did not decrease significantly. These results indicate that fasting has differential influences on immune function rather than a uniformly deleterious effect. Of potential import, this nutritional alteration appears to actually enhance certain effector functions of the host defense system.

Prostaglandin E1 inhibits T-cell proliferation and renal disease in MRL/1 mice.

Abstract MRL 1 mice develop an autoimmune, lupus-like disorder characterized by massive proliferation of T cells and rapidly fatal immune complex nephritis. Prostaglandin E1 (PGE1), in pharmacologic quantities, retarded the development of this syndrome. The beneficial effects included: (1) increased lifespan, (2) prevention of peripheral T lymphoid hyperplasia, (3) preservation of T-cell mitogenic responses, (4) inhibition of immune complex-mediated glomerulonephritis, and (5) reduction in the amounts of circulating gp70-anti-gp70 immune complexes and of IgG1 and IgG2b. These studies suggest that the protective effects of PGE1 are related to the inhibition of lymphoid hyperplasia and the consequent prevention of renal disease.

Age- and sex-related glomerulonephritis in New Zealand white mice

Abstract Both New Zealand white (NZW) and black (NZB) mice develop a form of clinically silent glomerulonephritis. In the former, the renal lesion is more pronounced in females and results from the deposition of immune complexes in glomeruli. The most prominent features of the lesions are deposits of immune complexes in the mesangium and an increase in the number of cells in glomeruli. More advanced lesions consisted of complexes in the peripheral capillary wall. By contrast, NZB mice showed only minimal sex differences; furthermore, their lesions were less advanced than in the NZW females. These data show that renal disease in the NZB/W hybrid is most similar to nephritis of the female NZW mouse.

Antibody responses to meningococcal polysaccharide vaccine in adults without a spleen

Asplenic persons are at risk for the development of overwhelming sepsis from certain encapsulated bacteria, including meningococci. Since it is not known if asplenic persons can have antibody responses, this study compared such responses following bivalent groups A and C meningococcal polysaccharide vaccine in 22 asplenic subjects and healthy control subjects. There were no adverse reactions to the vaccine. Antibody responses were measured using a solid-phase radioimmune assay; results were compiled for both seroconversions and changes in mean antibody titers of IgG, IgA, and IgM classes. Subjects who underwent splenectomy for trauma and control subjects with spleens showed a polyclonal antibody response to both vaccine antigens. Those persons who underwent splenectomy for nonlymphoid tumors had nearly as good a response as normal subjects. By contrast, asplenic subjects with lymphoid tumors who had received prior chemotherapy and radiotherapy had poor responses to both antigens. It is concluded that meningococcal vaccine is immunogenic in asplenic persons, with the aforementioned exceptions, and that this vaccine should be routinely administered to such persons.

Absence of immune deficiencies in a case of progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare disease related to a slow virus infection of the central nervous system; it is usually seen in patients who have impaired immunologic function. The present patient with biopsy-proved PML was found to have no demonstrable defects in either cellular or humoral immunity as assessed by multiple parameters. Thus, it appears that PML may occur in the presence of intact immune responses.

Acute Myeloblastic Leukemia and Hypercalcemia

Abstract We studied a patient with acute myeloblastic leukemia, hypercalcemia, hypophosphatemia and inappropriately elevated serum parathyroid hormone levels to define the mechanism of the hypercalcemia. On six occasions during two years, hypercalcemia occurred in conjunction with relapses of leukemia. Each time, serum calcium decreased to normal levels in parallel with reduction of the leukemic mass. During two periods of hypercalcemia, immunoreactive parathyroid hormone values were abnormally high. In addition, hormone was detected in vitro after short-term incubation of the leukemic cells (after 24 hours, the patients cells produced 129 pg of PTH per milliliter, whereas myeloblasts from a normocalcemic patient with leukemia produced only 33 pg). In freezethawing experiments, 39 pg of parathyroid hormone was released from 1 X 108 of the patients myeloblasts; no hormone was released from the normocalcemic cells. These findings suggest that the hypercalcemia resulted from ectopic parathyroid hormone pro...

Immunologic characterization of chronic lymphocytic leukemia cells

Immunologic characterization of the neoplastic cells in the circulation of patients with CLL suggests these cells show significant differences in membrane characteristics from normal B lymphocytes. Although the leukemic cells bear a homogenous membrane‐associated immunoglobulin, they also react with an anti‐human T cell serum. In all patients studied, 60–90% of the cells were stained by this antiserum. This suggests that the leukemic cells share antigenic determinants with T lymphocytes. CLL cells, unlike normal B cells, showed a marked increase in mouse‐complement receptors. No increase in receptors for guinea pig complement was observed in the leukemic cells. The population of SIg‐bearing lymphocytes was significantly greater than that of complement‐receptor bearing lymphocytes. The total number of E‐rosetting cells was increased in all CLL patients. Mitogenic responses of the leukemic cells were depressed and delayed. These results suggest that neoplastic lymphocytes cannot be classified as T‐ or B‐derived on the basis of criteria used to define normal lymphocytes.

Hematopoietic progenitor cell content of vertebral body marrow used for combined solid organ and bone marrow transplantation.

While cadaveric vertebral bodies (VB) have long been proposed as a suitable source of bone marrow (BM) for transplantation (BMT), they have rarely been used for this purpose. We have infused VB BM immediately following whole organ (WO) transplantation to augment donor cell chimerism. We quantified the hematopoietic progenitor cell (HPC) content of VB BM as well as BM obtained from the iliac crests (IC) of normal allogenic donors (ALLO) and from patients with malignancy undergoing autologous marrow harvest (AUTO). Patients undergoing WO/BM transplantation also had AUTO BM harvested in the event that subsequent lymphohematopoietic reconstitution was required. Twenty-four VB BM, 24 IC BM-ALLO, 31 IC AUTO, and 24 IC WO-AUTO were harvested. VB BM was tested 12 to 72 hr after procurement and infused after completion of WO grafting. IC BM was tested and then used or cryopreserved immediately. HPC were quantified by clonal assay measuring CFU-GM, BFU-E, and CFU-GEMM, and by flow cytometry for CD34+ progenitor cells. On an average, 9 VB were processed during each harvest, and despite an extended processing time the number of viable nucleated cells obtained was significantly higher than that from IC. Furthermore, by HPC content, VB BM was equivalent to IC BM, which is routinely used for BMT. We conclude that VB BM is a clinically valuable source of BM for allogeneic transplantation.

Acquired immunodeficiency syndrome in the child of a haemophiliac

Oral thrush developed during the second month of life in the 5-month-old son of a patient with haemophilia A. He did not feed well, and interstitial pneumonitis, lymphadenopathy, hepatosplenomegaly, and a cellular immune defect consistent with the acquired immunodeficiency syndrome (AIDS) followed. Both parents had signs of pre-AIDS during the year before their sons illness. Transmission presumably occurred in 3 steps: parenterally, via factor VIII concentrate in the haemophiliac; heterosexually, from the haemophiliac to his wife; and vertically, from mother to infant, or via close paternal-infant or maternal-infant contact. This first report of AIDS in the child of a haemophiliac supports the theory that AIDS is caused by an infectious agent. Concentrate-treated haemophiliacs may transmit this agent to their spouses or children, resulting in pre-AIDS or AIDS.