Allogeneic mixed lymphocyte reactions during a second round of ontogeny: normal accessory cells did not restore defective interleukin- 2 (IL-2) synthesis in T cells but induced responsiveness to exogeneous IL-2

Abstract

The T-cell-accessory-cell interaction in mixed lymphocyte cultures was investigated in 25 patients following autologous bone marrow transplantation (ABMT) using autologous bone marrow treated in vitro with the cyclophosphamide derivative ASTA Z 7557. In a previous study using the same group of patients, T cells failed to synthesize interleukin-2 (IL-2) and proliferate in response to CD3- and CD2- mediated stimuli even in the presence of exogenous IL-2. To investigate whether this defect in IL-2 synthesis and proliferation was caused by defective cell-to-cell interactions, we analyzed mixed lymphocyte reactions (MLR) using T cells and irradiated non-T cells. When normal T cells from 10 different healthy subjects were challenged with allogeneic normal non-T cells, IL-2 production and proliferation were observed. In contrast, when normal T cells were cultured with non-T cells derived from patients found between 20 and 330 days after ABMT, no IL-2 secretion and no proliferative responses could be seen. The addition of lymphokines such as interleukin-1 (IL-1), interleukin-3 (IL- 3), tumor necrosis factor (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon-gamma (IFN-y) did not improve the reactions. Furthermore, when patients' T cells were incubated with normal, irradiated non-T cells, defective IL-2 synthesis or proliferative response was obtained. However, when IL-2 was added to these cultures, an improvement in proliferative reactions was observed. Taken together, these new data provide additional evidence that T cells early in ontogeny possessed an intrinsic defect in IL-2 synthesis and that physical cell-to-cell contact between patients' T cells and allogeneic accessory cells induced functional responsiveness to exogeneous IL-2.

Mesenchymal Stromal Cells for Transplant Tolerance

“…Among mediators involved in T REG induction, the trophic cytokine IL-2 seems to be critical for the whole process to occur (140, 141): since neither MSC nor T REG secrete IL-2, the concentration of this cytokine relies on conventional T-cell production. Studies on the kinetics of IL-2 secretion during effector T-cell differentiation elucidated how terminal effectors progressively lose their ability to secrete this cytokine (142), resulting in a steep decline in IL-2 concentrations after 2 days in a conventional MLR (143). Thus, it is tempting to speculate that MSC may fail to induce T REG from terminally differentiated conventional T cells due to low IL-2 concentrations, but other concomitant factors are likely to play a role.…”

Reconstitution of the immune system after hematopoietic stem cell transplantation in humans

“…G-CSF mobilized PBSC grafts contain a large number of monocytes [approximately two logs more than marrow grafts (8)] but most of the monocytes infused with PBSCs probably either die or become tissue macrophages within days because monocytes in the blood of PBSC recipients become virtually undetectable by day 7 (Storek, unpublished). The function (e.g., IL-1 production or antigen presentation) of the recovering monocytes may be subnormal for approximately a year (34,35), though several studies suggest normal function already early posttransplant (36-38).…”

Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation

“…Though the innate immune system quantitatively recovers in the first weeks after HCT, these cells may not be functionally competent. Indeed, functional recovery of the hematopoietic innate immune system typically occurs in the 4–12 months after transplant [ 17 , 24 , 25 ]. The adaptive immune system, including the cellular immune response and humoral immune response, requires functional T-lymphocytes and B-lymphocytes.…”

“…Further, T-cell immune reconstitution requires a functional thymus and, thus, may be significantly limited in older patients who can have thymic atrophy [ 29 ]. HLA matched donors have also been shown to yield better immune reconstitution, possibly because HLA mismatched may lead to more mixed lymphocyte reactions and host-versus-graft alloreactivity that can delay immune reconstitution [ 25 , 33 , 34 ]. More intensive conditioning regimens can result in more rapid engraftment, though may also slow early lymphocyte recovery [ 35 ].…”