Hideto Kaneshima

HUMAN HEMATOLYMPHOID CELLS IN SCID MICE

The severe combined immunodeficient C.B.-17 scid/scid (SCID) mouse has been widely used to study the normal processes of murine lymphoid differentiation. To create an in vivo model of the human hematolymphoid system, this mouse strain has been engrafted with human organ systems (the SCID-hu mouse) or with human peripheral blood mononuclear cells (the hu-PBL-SCID mouse). These mouse models have now been characterized and used to analyze human infectious diseases, hematopoiesis, malignancies and vaccines.

Strains of Measles Vaccine Differ in Their Ability to Replicate in and Damage Human Thymus

A number of strains of live attenuated measles virus are in use worldwide as measles vaccines. All effectively induce protective immunity, but many differences in immunogenicity and, potentially, in safety are seen between strains in young infants. However, no system for assessing biologic differences between vaccine strains has been available. The SCID-hu thymus model system was used to compare AIK-c, Edmonston-Zagreb (EZ), and Moraten-3 common vaccine strains derived from the Edmonston prototype virus-for replication and pathologic changes in human thymus. EZ replicated best and induced substantial thymocyte death; AIK-c replicated poorly but induced moderate thymocyte death; Moraten replicated moderately well but did not affect thymic architecture. Thus, live attenuated measles vaccines differ in replicative capacity and pathogenicity in vivo. These differences may account for strain-dependent variations in immunization.

THE HEMATOPATHOLOGY OF HIV-1 DISEASE: EXPERIMENTAL ANALYSIS IN VIVO

The human immunodeficiency virus (HIV-1) is the etiologic agent of the acquired immune deficiency syndrome (AIDS). As the AIDS epidemic has spread worldwide, the prevailing focus has been on several salient features: first, that the disease is acquired (how can it be avoided?), and secondly, that it results in immunodeficiency (what are the immunopathologic correlates and how can they be reversed?). Far less attention has been devoted to the fact that HIV-1 infection produces a syndrome in which immunodeficiency is but one manifestation. Given the dramatic presentation of visibly end-stage patients, this emphasis is clinically sound. In terms of understanding pathogenesis, however, it is less useful. By analogy, the mechanistic basis of hypertension is not understood upon analysis of its end-stage sequelae: strokes and myocardial infarcts; likewise, the presentation of ketoacidosis does not immediately suggest a pancreatic β-cell defect in insulin production. To understand the syndrome of HIV-1 disease, it is perhaps more appropriate to expand our preclinical studies towards the basic pathogenic mechanisms of the virus which occur early in the course of disease, and which eventually lead to the clinical manifestations of immunodeficiency, wasting, neurological disorders, etc. In this manner, common reducible pathways may be delineated which would allow treatments to prevent late stage AIDS.

Differing functional recovery of donor-derived immune cells after purified haploidentical and fully mismatched hematopoietic stem cell transplantation in mice

Functional recovery of the immune system is critical for long-term survival in hematopoietic stem cell transplant recipients. In this study, two donor-recipient allogeneic transplant settings (haploidentical and fully mismatched) are used to investigate the functional activity of donor-derived B and T cells in animals grafted with purified c-kit(+), Thy 1.1(lo), Lin(-/lo), and Sca-1(+) hematopoietic stem cells (KTLS HSC).Ovalbumin-specific immunoglobulin G, polyclonal immunoglobulin isotypes, and B- and T-cell proliferation were examined on the recipients who received haploidentical or fully mismatched HSC.A severe deficiency of antigen-specific immunoglobulin response occurs in fully engrafted mice that received KTLS HSC from fully mismatched, but not haploidentical, donors. This lack of B-cell-specific immunity is not due to a deficiency of polyclonal immunoglobulins in serum. B cells from both fully mismatched and haploidentical recipients proliferate normally after stimulation with anti-mu and the percentage of mature B cells is normal. The T-cell response to anti-CD3 in fully mismatched recipients was much weaker than that of their untransplanted controls. However, T cells from haploidentical recipients respond normally to anti-CD3. This study demonstrates that numerical recovery of donor-derived cells in the periphery of recipients does not represent a functional reconstitution, particularly in animals that receive fully mismatched transplants. Defects of specific B-cell immunity and T-cell proliferation are observed in fully mismatched, purified HSC transplant recipients with a quantitative recovery within the normal range of donor-derived lymphocytes.