Biomedical subjects

Yide Jin

Publications and source records attributed to Yide Jin.

5 recordsLinked to original sources

PubMed2005

Campath-1H does not alter bone marrow cell regulatory function.

We have previously reported in laboratory volunteers (in vitro) and renal transplant recipients (ex vivo) that bone marrow cells (BMC) are potent downregulators of the immune response. Also, the use of alemtuzumab (Campath-1H, C1H) for immunodepletion is associated with the most potent lasting effects yet seen on T-cell immunity in renal transplantation. We questioned whether the administration of C1H to kidney allograft recipients of donor bone marrow cell (DBMC) infusions would lead to stronger or weaker immunoregulatory effects. Human BMC depleted of T cells (nT-BMC) were either untreated or treated with C1H and rabbit complement and compared for their ability to downregulate autologous or allogeneic T-cell responses and to generate T regulatory (T reg) cells. The proliferative responses to anti-CD3 monoclonal antibody of T cells derived from cocultures with C1H-treated or untreated autologous nT-BMC were equally suppressed, i.e., an equivalent alteration in CD3 complex signaling, not regained by the addition of interleukin 2. Adenosine triphosphate levels were also markedly reduced in T cells both from C1H-treated and untreated nT-BMC cocultures. The ability of C1H-treated or untreated nT-BMC to suppress autologous T-cell cytotoxic function was also equivalent, with a marked, but equivalent, capacity to induce CD4/CD25(high) T regs from CD3(+) cells, which effectively downregulated cytotoxic T cells. To mimic the clinical infusion of DBMC into (allogeneic) recipients, peripheral blood mononuclear cells were also cultured with allogeneic C1H-treated and untreated nT-BMC. T cells derived from these cultures secondarily stimulated with the same-donor mature antigen-presenting cells exhibited suppressed cytotoxicity by 85% and 54%, respectively. These in vitro studies suggest that C1H does not abrogate BMC immunoregulation and thus may allow its lympho-depleting effect to be synergistic.

Alemtuzumab↗

PubMed2004

Donor bone marrow infusion in deceased and living donor renal transplantation.

The infusion and persistence in a transplant recipient of donor-derived bone marrow cells (DBMC) of multi-lineage can lead to a state of permanent chimerism. In solid vascular organ transplantation, the donor bone marrow lineage cells can even be derived from the transplant organ, and these cells can be detected in very small numbers in the recipient. This has been called microchimerism. Much controversy has developed with respect to the function of chimeric cells in organ transplantation. One idea is that the occurrence of these donor cells found in microchimerism in the recipient are coincidental and have no long-term beneficial effect on engraftment. A second and opposing view, is that these donor cells have immunoregulatory function that affect both the acute and chronic phases of the recipient anti-donor responses. It follows that detecting quantitative changes in chimerism might serve as an indication of the donor-specific alloimmune or regulatory response that could occur in concert with or independent of other adaptive immune responses. The latter, including autoimmune native disease, need to be controlled in the transplant organ. The safety and immune tolerance potential of DBMC infusion with deceased and living donor renal transplants was evaluated in a non-randomized trial at this center and compared with non-infused controls given identical immunosuppression. Overall DBMC infusions were well tolerated by the recipients. There were no complications from the infusion(s), no episodes of graft-vs-host disease (GVHD) and no increase infections or other complications. In the deceased DBMC-kidney trial, actuarial graft survival at 5 years was superior especially when graft survival was censored for recipient death. Acute rejections were significant reduced in patients given two DBMC infusions, and chronic rejection was dramatically reduced in all DBMC treated patients. The most interesting finding was that the degree of microchimerism slowly increased over the years the DBMC group that had exhibited no rejection episodes. In the DBMC-living related trial, the incidence of acute rejection did not differ between groups. However, DBMC chimerism in recipient iliac crest marrow had increased more rapidly than might be predicted from results previously seen in the cadaver group, despite four times fewer DBMC infused, with the generation of T- regulartory cells in-vitro assays.

Bone Marrow Transplantation↗

PubMed2004

Antigen presentation and immune regulatory capacity of immature and mature-enriched antigen presenting (dendritic) cells derived from human bone marrow.

Several reports including those from this laboratory have demonstrated that bone marrow cells (BMC) downregulate in vitro both mixed leukocyte reaction and cytotoxic T lymphocyte reactions. We consequently hypothesized that a general property of immature cells of hematopoietic organs is their ability to suppress immune reactivity. As one of these suppressive activities, the lack of costimulatory molecules was proposed as a mechanism by which immature antigen presenting cells of the bone marrow might be involved. In the present report, we used two culture environments, each of which would regulate a different maturation pattern of human bone marrow-derived enriched dendritic antigen presenting cells (DC or APC) to determine the respective effects on in vitro immune regulatory function. Human BMC depleted of CD3+ cells were cultured with either: interleukin-4 (IL-4) and granulocyte macrophage-colony stimulating factor (GM-CSF), to maintain DC-enriched populations in an immature state (iAPC); or an interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNF-alpha), GM-CSF, LPS, and IL-6 cocktail to promote the maturation of DC-enriched APC (mAPC). These iAPC and mAPC were, respectively, phenotypically characterized and also tested in vitro for the following: (1) both direct and indirect-antigen presentation functions; (2) immune regulatory functions on the response of autologous and allogeneic peripheral blood lymphocytes (PBL); and (3) Western blot analysis determining the levels of both major histocompatibility complex (MHC) class I related cytoplasmic transporter molecules associated with antigen processing (TAP1) and as well as proteasome activator molecules (PA28alpha). The iAPC population expressed fewer dendritic cell markers (CD83 and DCsign), and costimulator molecules (CD86 and CD40) than the mAPC, such that there was an approximate threefold increase in expression of CD83, 2.5-fold increase in DCsign, and a threefold increase in CD40 and CD86 on mAPC than on iAPC (p=0.005 for CD83; p=0.001 for DCsign; p=0.001 for CD86; and p=0.001 for CD40). In lymphoproliferative assays, indirect and direct alloantigen presentation by iAPC was weaker than by mAPC (p=0.05 and 0.04). In addition, iAPC were able to downregulate allogeneic CTL responses. Also, after pulsing with Epstein-Barr virus (EBV) protein antigens, the iAPC were less efficient in their presentation to autologous EBV-specific T-cell lines, and caused an inhibition of EBV-CTL generation. The expression of TAP1 and PA28alpha was reduced in iAPC in comparison to mAPC. These findings support the notion that a maturation state of BMC-derived APC correlates with their capacity to present antigen. The observed in vitro deficiency of this function by immature bone marrow cells may therefore contribute to the immune downregulatory capacity seen in the BMC compartment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Functional and phenotypic properties of peripheral T cells anergized by autologous CD3(+) depleted bone marrow cells.

We have previously demonstrated that bone marrow cells (BMC) inhibit the generation of autologous Epstein-Barr virus (EBV) -specific cytotoxic T lymphocytes (CTL). It was also observed that CD3(+) cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV-CTL generation. In the present study, we examined these BMC induced regulator CD3(+) T cells with respect to phenotype, function, and T-cell activation pathways. We also questioned if the CD3(+) regulatory cell function is mediated by their direct effect on peripheral T cells or on the ability of antigen presenting cells (APC) to stimulate peripheral T cells. To answer this, CD3(+) cells from peripheral blood lymphocytes (PBL) were cultured with either CD3-depleted BMC or with CD3-depleted PBL. The CD3(+) cells were then isolated with immunomagnetic beads, designated as T(BM) and T(PBL), and were compared in functional studies. There was an increase in the expression of CD25 on T(BM) cells. The T(BM) cells also expressed less CD122 and a decreased number of CD3 molecules per cell. Both T(BM) and T(PBL) cell populations responded to mitogen (PHA) to the same magnitude. However, when stimulated through the CD3 complex with anti-CD3 monoclonal antibody (mAb), the T(BM) cells had a significantly decreased response than did T(PBL). The addition of IL-2 to these latter cultures augmented, but could not fully restore, the response. Additionally, stimulation of T(BM) cells with allogeneic cells failed to produce cytotoxic T cells. These "anergized" T(BM) and "nonanergized" (control) T(PBL) cells were added as third-party cells to a CTL generating culture of autologous PBL stimulated with allogeneic cells. The T(BM) cells exhibited suppressor function and inhibited the generation of CTL, in contrast with T(PBL). The effect of T(BM) cells on direct and indirect antigen presentation pathways demonstrated that T(BM) primarily effected indirect, but not direct, alloantigen presentation. To further explore the cytoplasmic T-cell activation events that occurred after the coculture of the PBL T cells with BMC, the levels of zeta-associated protein 70 (ZAP70) and extracellular receptor-activated kinase (ERK) were determined. There was a decrease in ZAP70 levels in the T(BM), which correlated with its reduced expression of cell surface CD3 and the attenuated response to anti-CD3 mAb activation. However, the activity of ERK was equally expressed by T(BM) and T(PBL). It, therefore, appears that the culturing of peripheral T cells with (non-T) BMC anergizes these cells (which become refractory to stimulation through the T-cell receptors), and induces immune suppressor function. These in vitro observations may provide a mechanism by which infused donor BMC serve to downregulate T-cell immunity.

Antigen Presentation↗

PubMedDate not supplied

Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation.

Infusions of donor bone marrow derived cells (DBMC) continue to be tested in clinical protocols intended to induce specific immunologic tolerance of solid organ transplants based on the observations that donor-specific tolerance is induced this way in animal models. We studied the immunological effects of human DBMC infusions in renal transplantation using modifications in lymphoproliferation (MLR) and cytotoxicity (CML) assays. The salient observations and tentative conclusions are summarized in this review. Among many types of organs transplanted using DBMC at this center, it was found that the cadaver renal recipients (CAD) had significantly decreased chronic rejection and higher graft survival when compared to equivalent non-infused controls. DBMC infusion was also associated with a marginal and non-specific immune depression. It was also observed that the number of chimeric donor cells gradually increased in the iliac crest bone marrow compartment with a concomitant decrease in the peripheral blood and that the increase was more rapid in living-related donor (LRD)-kidney/DBMC recipients in spite of a lower number of DBMC infused (<25%) than in the CAD-kidney/DBMC group. In the LRD recipients with residual anti-donor responses, purified chimeric cells of either donor or recipient inhibited recipient immune responses to the donor significantly more strongly than the freshly obtained bone marrow from the specific donor or volunteer suggesting an active regulatory role for chimeric cells. A number of (non-chimeric) subpopulations of bone marrow cells including CD34(+) stem cells and the CD34(-) early progeny like CD38(+), CD2(+), CD5(+) and CD1(+) lymphoid cells as well as CD33(+) (but CD15(-)) myeloid cells down-regulated the MLR and CML responses of allogeneic PBMC stimulated with (autologous) donor spleen cells. These regulatory effects appeared to be refractory to the action of commonly used immunosuppressive drugs and occurred during the early phase of the immune response through cell-cell interactions. Most of these DBMC sub-populations had stimulatory capabilities, albeit markedly lower than donor spleen cells, but only through the indirect antigen presentation pathway. When co-cultured with allogeneic stimulators, purified CD34(+) cells were found to give rise both to CD3(-) TCRalphabeta(+), as well as CD3(+) TCRalphabeta(+) cells and, thereby, responded in MLR to allogeneic stimulation (but did not generate cytotoxic effector cells). Also, a number of DBMC subpopulations inhibited the CML and to a lesser extent the MLR, of autologous post-thymic responding T cells stimulated with allogeneic irradiated cells, mediated through soluble factors. Finally, non-chimeric DBMC also inhibited the proliferative and cytotoxic responses of autologous T cells to EBV antigens, inducing T suppressor cells, which in turn could inhibit autologous anti-EBV CTL generation and B cell anti-CMV antibody production. These studies all suggested a strong inhibitory property of a number of DBMC sub-populations in vitro and in vivo with the notion that they promote unresponsiveness.

Bone Marrow Cells↗