Correlation between the numbers of naive T cells infused with blood stem cell allografts and the counts of naive T cells after transplantation.

Naive T cells after allogeneic hematopoietic cell transplantation are thought to originate from the engrafted hematopoietic cells. In this report, we show that there is a correlation between the number of naive CD4 T cells infused with peripheral blood stem cell grafts and the absolute number of peripheral naive CD4 T cells on day 30 (R = 0.65; P <.001), day 80 (R = 0.63; P <.001), and day 180 (R = 0.66; P <.001) after transplantation. These results suggest that in the first 6 months after transplantation, most naive CD4 T cells are derived from the naive T cells infused with the graft.

Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys.

In mice, interleukin-7 (IL-7) hastens T-cell reconstitution and might cause autoimmune diseases, lymphoma, and osteoporosis. We assessed the effect of IL-7 on T-cell reconstitution and toxicity in baboons that underwent total body irradiation followed by autologous transplantation of marrow CD34 cells. Three baboons received placebo and 3 baboons received recombinant human IL-7 (rhIL-7, 75 microg/kg twice a day subcutaneously) between 6 and 10 weeks after transplantation. The mean increase in blood absolute CD4 T-cell counts was 0.9-fold in the placebo-treated animals versus 9.0-fold in those treated with IL-7 (P =.02). The increase observed in the IL-7-treated animals appeared attributable to peripheral expansion rather than de novo generation. The IL-7-treated animals had greater mean increases in the volumes of the spleen (2.0-fold with placebo versus 4.5-fold with IL-7, P =.02) and lymph nodes (1.8-fold with placebo versus 4.1-fold with IL-7, P =.10) but not the thymus (3.4-fold with placebo versus 1.1-fold with IL-7, P =.18). Side effects of IL-7 included thrombocytopenia and possibly neutropenia and hemolytic anemia. One IL-7-treated animal failed to thrive due to a disease resembling graft-versus-host disease. No animals developed lymphoma. Bone density was not decreased. In conclusion, IL-7 raises CD4 T-cell counts in irradiated primates. It remains to be determined whether this is associated with clinical benefit.

Factors affecting antibody levels after allogeneic hematopoietic cell transplantation.

To obtain insight into the mechanism(s) of posttransplantation humoral immunodeficiency, we evaluated factors affecting serum antibody levels against polio, tetanus, Haemophilus influenzae, and Streptococcus pneumoniae in 87 patients. Patients with hematologic malignancies were randomized to receive marrow versus blood stem cells, which contain approximately 10 times more lymphocytes than marrow. Blood stem cell recipients did not have higher antibody levels than marrow recipients. Recipient pretransplantation antibody levels were correlated with the posttransplantation levels, especially in the first 6 months after transplantation when the correlation coefficients typically exceeded 0.6. Donor pretransplantation antibody levels had less of a correlation with posttransplantation levels in the recipient. Patient or donor age, total body irradiation, and graft-versus-host disease or its treatment appeared to have no effect. In conclusion, antibody levels in the first year after transplantation are affected primarily by pretransplantation antibody levels in the recipient and, to a lesser degree, in the donor. These findings suggest that immunization of the recipient and the donor before transplantation may be more effective in improving antibody immunity after transplantation than manipulating graft-versus-host disease, changing conditioning, or increasing the number of lymphocytes in the graft.

Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation.

In adult recipients of allogeneic hematopoietic cell transplants (HCT) studied at 1 year after grafting, there was a significant correlation between the counts of T cell receptor excision circle (TREC)-containing CD4 T cells (presumed recent thymic emigrants) and the counts of total T cells (r=0.65, P<0.001). Thus, the reconstitution of CD4 T cell pool depends on T cell generation from hematopoietic stem cells (T-lymphopoiesis). We evaluated factors that could affect T-lymphopoiesis. Low TREC-containing CD4 T cell counts were associated with older patient age (r=-0.41, P=0.01) but not with donor age, graft type (marrow vs. blood stem cells), CD34 cell dose, conditioning (with vs. without irradiation), acute graft-versus-host disease (aGVHD), or chronic graft-versus-host disease (cGVHD) in multivariate analysis. We conclude that patient age is the primary determinant of CD4 T-lymphopoiesis after allogeneic HCT.

Kinetics of B, CD4 T, and CD8 T cells infused into humans: estimates of intravascular:extravascular ratios and total body counts.

Little is known about the rate of T and B cell traffic from blood to extravascular compartments or about the steady-state distribution of T and B cells between intravascular and extravascular compartments in humans. We quantitated circulating T and B cell subsets before and during the first 24 h after the infusion of an allogeneic or syngeneic peripheral blood stem cell graft (containing approximately 10(10) lymphocytes) into 10 patients conditioned with chemotherapy and/or total body irradiation. For all lymphocyte subsets measured, <15% of the infused cells were present in the blood at the end of the 0.5-h infusion and <3% of the infused cells were present in the blood 1 h later. Thereafter, CD4 T cell counts plateaued at approximately 1% and CD8 T cell counts at < or = 0.4% of the infused cells, whereas B cell counts declined slowly (1.5% of the infused B cells were present in the blood at 2 h and 0.3% at 24 h postinfusion). We conclude that the rate of lymphocyte traffic from blood to extravascular spaces can be extraordinary (approximately 10(10) lymphocytes can leave blood within 0.5 h) and that at steady state the blood contains approximately 1% total body CD4 T cells, < or = 0.4% total body CD8 T cells, and approximately 1.4% total body B cells. By inference, an average-size person may carry a total of approximately 4.1 x 10(11) CD4 T cells, > or = 4.5 x 10(11) CD8 T cells, and approximately 1.0 x 10(11) B cells.