Humoral and cell-mediated immune responses in fully allogeneic bone marrow chimera in mice

Abstract

AKR mice were protected from lethal irradiation and established as long-lived chimeras by transplanting allogeneic C57BL/6 (B6) bone marrow that had been treated in vitro with anti-Thy-1 antiserum without complement. In these chimeras, which were designated [B6 {arrow} AKR], virtually all the thymus and spleen cells were shown to be derived from the B6 donor; several immune functions studied in these chimeras were as follows: (a) The chimeric mice were tolerant of histocompatibility antigens of both donor and recipient strain and nearly fully reactive to antigens of third party, as revealed by Simonsen's splenomegaly assay. The tolerance of these chimeras could not be attributed to suppressor cells but was compatible with clonal depletion. (b) Proliferative responses to concanavalin A, phytohemagglutinin, and lipopolysaccharide as well as natural killer and antibody-dependent cell- mediated cytotoxicity activity of the chimeric mice was normal. (c) Plaque- forming cell (PFC) assays of antibody responses to sheep erythrocytes (SRBC) showed gross deficiency in the primary response of the [B6 {arrow} AKR] and [AKR {arrow} B6] chimeras. By contrast, [B6-H-2(k)(E(k)) {arrow} AKR] H-2-compatible chimeras and [AKR {arrow} AKR] syngeneic marrow transplanted mice had normal primary PFC responses. PFC responses after secondary stimulation with SRBC, however, revealed vigorous direct plaque formation and substantial but somewhat smaller indirect plaque formation in the [B6 {arrow} AKR] chimeras. This observation favors operationally the concept of adaptive differentiation proposed by Katz et al. (44). (d) Analysis of ability of the chimeras to develop and express delayed-type hypersensitivity responses to contact sensitizer (2,4-dinitro-l-fluorobenzene [DNFB]) showed no apparent immunodeficiency of either chimeras to this form of immunization. Development of immunologic tolerance to DNFB, however, was grossly deficient in [B6 {arrow} AKR] chimeras but normal in [AKR {arrow} AKR], [B6 {arrow} B6], and [E(k) {arrow} AKR] chimeras. These findings indicate that full chimeras across major histocompatibility complex have considerable immunologic vigor even though primary immune responses that require histocompatibility between interacting cell types are initially defective.

Comparative Analyses of Thymocyte and Thymic Low‐Density Adherent Cell Functions

“…Thymic LDAC as well as thymocytes of the BM chimeras were fully reconstituted by cells derived from donor BM as described previously (22,24,28,42,57). In general, macrophage functions (phagocytosis, esterase activity, expression of Fc or C3 receptors, and granuloma formation) in peripheral tissues are intact in BM chimeras (25,26,57).…”

Expansion of Myeloid Suppressor Cells in SHIP-Deficient Mice Represses Allogeneic T Cell Responses

“…As described previously, these hosts were irradiated with 9.5 Gy from a 137 Cs source, transplanted with 5 ϫ 10 6 BALB/c (H2 d ) whole BM cells, and monitored for signs of acute GvHD post-transplant as previously described (9). BM donors were not exsanguinated before BM harvest, because this eliminates peripheral T cells from whole bone marrow grafts that are necessary for acute GVHD in this transplant setting (15)(16)(17). Before transplant, mice were housed in a nonbarrier, but specific pathogen-free, facility at the Moffitt Research Center vivarium.…”

Induced SHIP Deficiency Expands Myeloid Regulatory Cells and Abrogates Graft-versus-Host Disease

“…As shown by Good and colleagues (34), humoral immune responses to T-dependent Ags are severely compromised following allogeneic BMT. Consistent with this seminal study in a murine allogeneic BMT model, recovery of B cell function and Ab responses to pathogens is frequently delayed or permanently compromised in clinical allogeneic BMT patients (35)(36)(37)(38) and contributes to posttransplant morbidity (39).…”