Thymus dependency of bone marrow stem cell proliferation in response to certain antigens.

The activity of mouse bone marrow CFU's following systemic injection of antigen has been investigated. In normal mice quiescent CFU's may be triggered into cycle after antigenic challenge. Prior adult thymectomy prevents stimulation of CFU if thymus-dependent antigens are injected but not when thymus-independent antigens or non-specific stimuli are used. Similar results were obtained in congenitally athymic mice. This seems to indicate an independent pathway for CFU triggering for each cell lineage and for T and B cells.

On the sparse seeding of bone marrow and thymus in radiation chimaeras.

The repopulation of the thymus was studied in mice after a potentially lethal dose of irradiation and injection of different numbers of syngeneic but chromosomally distinguishable bone marrow cells. The more bone marrow cells were injected, the earlier was the changeover from dividing host cells to dividing donor cells observed. At both 30 and 60 days after irradiation, the number of donor-derived T cells in the peripheral blood responding to phytohemagglutinin was directly proportional to the number of donor bone marrow cells injected, but the number of host-derived T cells was inversely proportional. Experiments in which mistures of two syngeneic chromosomally distinguishable haematopoietic cell populations were injected after irradiation suggested that relatively small numbers of haematopoietic cells can be responsible for repopulating a single femur. Analysis of the thymus showed that the dividing cell populations within the thymus can also derive from very few precursor cells, possibly as few as one or two.

Effects of irradiation, anti-thymocyte serum and corticosteroids on PHA and LPS responsive cells of the mouse.

Peripheral lymphocytes responsive to stimulation by phytohaemagglutinin (PHA) and bacterial lipopolysaccharide (LPS) in culture have been quantitated following treatment of mice with anti-thymocyte serum (ATS), total body irradiation or corticosteroids. The ATS reduced the number of PHA-responsive cells in both blood and spleen, and induced splenomegaly, but it had little deleterious effect on spleen-borne LPS-responsive cells. In contrast, the spleens of mice treated with hydrocortisone acetate were atrophied and the remaining cells had a reduced LPS response and an enhanced PHA response. Total body irradiation impaired both PHA and LPS responsiveness in the spleen. Recovery of PHA responsiveness after either irradiation or ATS treatment was prolonged and was dependent on the presence of an intact thymus; recovery of LPS responsiveness after corticosteroid treatment was more rapid and was thymus-independent.

Studies of hyperthymic mice. II. The influence of thymus grafts on cell flow through the peripheral T-cell pool.

In normal CBA/H mice implanted under the kidney capsule with eight CBA/H.T6T6 neonatal thymus lobes it was observed that the percentage of marked thymus-graft derived T cells in the periphery, after building up to a peak, showed a biphasic exponential decline. The initial decline was very rapid and appeared to be due to loss of the thymus-graft derived cells from the system. The later decline was slower and was the same as that of an introduced cohort of lymph-node lymphocytes. The second rate of decline was, however, considerably more rapid than that of lymph-node cohort in non thymus-grafted mice. We conclude that in multiply thymus-grafted mice the flow of cells through the T-cell pool is more rapid than in normal mice and that in this sense the thymus can be thought to drive the lymphoid system.

The mitotic activity of, and antibody production by, sensitized lymphocytes quantified after transfer into irradiated recipients.

Adult thymectomized, irradiated CBA mice were reconstituted with bone marrow and thymus grafts derived from congenic strains differing in immunoglobulin allotype. After challenge with heterologous erythrocytes the allotype of the antibody secreted by the chimaeric spleen cells was the same as that of the bone marrow donor. When mixtures of immune and non-immune cells from the two congenic strains were transferred to irradiated recipients, a preponderance of the immune-donor cells was found dividing in the recipients' spleen 3 days after challenge with the immunizing antigen, and the allotype of the antibody-producing cells 7 days after challenge was almost entirely of immune-donor derivation. Further quantitative studies on the number of mitotically reactive cells observed after immunization with heterologous erythrocytes indicate that after primary and secondary challenge the mitotic activity of these cells is increased respectively four and eight times relative to that found in unsensitized cells.

The immunological response of CBA mice to P. yoelii. II. The passive transfer of immunity with serum and cells.

CBA mice infected with the malaria parasite Plasmodium berghei yoelii (P. yoelii) develop a self-resolving infection lasting 15-18 days; on recovery from a primary infection they are immune to further infection. Cell and serum transfers from immune to non-immune mice were used to analyse the mechanism of resistance. Whereas serum from mice which had recovered from a single infection was ineffective in transferring immunity, hyperimmune serum (from mice repeatedly challenged with P. yoelii) protected against challenge inocula of 10(4) and 5 X 10(4) but was ineffective against higher inocula (10(5)). Doses of serum which completely protected intact mice were ineffective when administered to T-cell deprived recipients. The injection of spleen cells from recovered mice conferred immunity on both normal and T cell deprived mice. Pretreatment of immune cell donors with cyclophosphamide reduce the ability of spleen cells to transfer immunity. Treatment of the immune cells with an anti-Thy 1 antiserum and complement in vitro did not abrogate their protective effect. The significance of these results is discussed in relation to the effector mechanisms which might operate in murine malaria.

Studies of hyperthymic mice. I. The influence of multiple thymus grafts on the size of the peripheral T cell pool and immunological performance.

Following the implantation of syngeneic chromosomally marked thymuses under the kidney capsule of normal adult mice, donor T cells were found in the blood and other lymphoid organs. The mice were found to have increased numbers of Thy.1-positive cells in spleen and lymph nodes, increased peripheral blood lymphocyte levels and also augmented immune responses to sheep erythrocytes. The contribution made by an individual graft to the donor T cell pool was independent of the number of thymuses grafted as was the growth of the grafts themselves. The results reaffirm that there is no homeostatic feedback control of thymus growth in adult mice.

Thymus graft reconstitution of T-cell-deprived mice infected with Trypanosoma musculi.

T-cell-deprived CBA mice were given thymus graft implants during the course of an infection with Trypanosoma musculi and at a time when the parasitaemia was high. As a consequence of the grafts, most of the mice survived the infection whereas control ungrafted mice died. In grafted animals there was generally a period of 60-80 days after grafting during which time parasitic numbers remained high, and a further period of 200 or more days when trypanosomes were still detectable in the circulation. The mice were highly variable in their responses and possible reasons for this are considered.

The effect of Rauscher and Moloney leukaemia virus on amyloid development in casein-treated CBA mice.

Infection of adult CBA mice with Rauscher or Moloney leukaemia virus concomitantly with caseination significantly accelerated spleen amyloid development in irradiated, bone-marrow protected mice, but had no effect on untreated, adult thymectomized or thymectomized irradiated mice. Spleen tissue of mice infected with Moloney virus had the highest titre in the mice with accelerated amyloid development.

Mechanisms for eosinophilic and neutrophilic leucocytoses.

Thymus-deprived mice are unable to react with eosinophilia to an appropriate stimulus, but their ability to mount a neutrophil leucocytosis in response to pyogenic infection is unimpaired. It appears that thymus-processed lymphocytes are required for induction of eosinophil but not of neutrophil leucocytosis.