Therapeutic immunology最新文献

The successful results seen after organ transplantation are largely attributable to the potency and specificity of modern immunosuppressive agents. Although drug-free unresponsiveness to graft alloantigens has not been routinely achieved in clinical practice, recent appreciation of the importance of cell chimerism, which develops after the migration from donor to host of leukocytes contained in solid organ grafts, has introduced a concept which may explain the mechanism of graft tolerance. Recent evidence has indicated that immunosuppressive drugs may have a common potential to induce graft tolerance, even though they act through diverse mechanisms, and that this potential may be mediated by a permissive effect on the migration and survival of donor-derived leukocytes. This review briefly examines the mechanisms by which immunosuppressive drugs function and analyses the different methods which these agents might use to induce chimerism associated with graft tolerance. Furthermore, we describe ongoing clinical studies in which the chimerism produced after solid organ transplantation is augmented with donor bone marrow in an attempt to facilitate the induction of tolerance.

We investigated the effects of FK506 and glucocorticoids (GC) on rat thymocytes using flow cytofluorometry. Rats were treated with GC (0.1 mg/body, by single injection), with FK506 (1 mg/kg/day, for 7 days), or with FK506 and GC. GC alone significantly decreased the percentage of CD4+8+ thymocytes and increased the percentages of CD4-8-, CD4+8- and CD4-8+ thymocytes on day 7. FK decreased the percentage of CD4+8- and CD4-8+ thymocytes and increased the percentage of CD4+8+ thymocytes on days 5 to 14. FK and GC induced a significant decrease in the number of CD4+8+ thymocytes greater than that seen with GC alone on day 7. The absolute number of TCR alpha beta high MHC class Ihigh thymocytes after FK and GC was significantly lower than that of the control group, and was slightly lower than that after FK alone on day 14. These results suggest that combined treatment with FK506 and GC acts complexly to decrease rat CD4+8+ thymocytes and prevents thymocyte differentiation and maturation.

One approach to adoptive cancer immunotherapy is based on the use of bispecific monoclonal antibodies (mAb) capable to redirect ex vivo generated cytolytic T lymphocytes (CTL) onto tumour cells. The efficiency of the CD28 T-cell activation pathway to induce CD3-dependent cytolytic activity was investigated while avoiding modulation of the TCR/CD3 complex needed for targeting by bispecific mAb. When used e.g. in conjunction with anti-CD2 antibodies or diacylglycerol derivatives, the in vitro stimulation of T cells with anti-CD28 mAb resulted within 36 h in high levels of CD3-dependent cytolysis (tested on a FcR+ target in the presence of anti-CD3 mAb) and sustained lymphokine production, such as TNF alpha, IFN gamma and IL-2, which may affect tumour growth when delivered locally by the transferred T cells. Rapid activation may reduce costly in vitro procedures, preserve homing capacities of retransfused T cells, and thus facilitate implementation of clinical trials based on the use of bispecific antibodies.

The effect of recombinant human tumour necrotic factor-alpha (TNF-alpha) on the intratumour and whole-body distributions of 90Y-labelled C110 anticarcinoembryonic antigen (CEA) monoclonal antibody (MAb) was studied using nude mice bearing two different tumours. The nude mice were injected subcutaneously with the CEA-positive LS174T colorectal cancer xenograft and the CEA-negative H-MESO-1 malignant mesothelioma xenograft. One hour before injection of radiolabelled MAb, mice were injected intravenously with human recombinant TNF-alpha (3 mg per mouse) or saline, and biodistributions of radiolabel were determined by tissue counting and whole-body autoradiography (ARG). Twenty-four hours after injection, TNF-alpha administration increased radioactivity in the LS174T tumour by 57% (17.30 +/- 1.61 vs. 9.83 +/- 1.55% ID g-1, P < 0.01), while decreasing radioactivity in blood and other normal organs. Diminished but similar effects on radioantibody biodistribution were seen at 48 and 72 hours. TNF-alpha did not affect specific MAb localization in the control H-MESO xenograft. Tumour:blood ratios were increased from 0.7 to 1.7 at 24 h with TNF-alpha administration. Pretreatment with TNF-alpha may be of value in increasing specific localization of monoclonal antibodies in tumour tissue.

Anti-CD5 ricin A chain immunoconjugate (XZ-CD5) is an immunotoxin that inhibits proliferative and cytotoxic responses to alloantigen in vitro and has activity in the treatment of acute graft-vs.-host disease (GVHD). To determine if XZ-CD5 could be used to prevent acute GVHD, 11 adult recipients of HLA-identical allogeneic marrow received XZ-CD5 0.1 mg kg-1 day-1 intravenously with high-dose methyl-prednisolone for 10, 14 or 17 doses early post-transplant. Six additional patients received 17 doses of XZ-CD5 and cyclosporine (CSA). All patients engrafted. Severe capillary leak syndrome was the most common serious toxicity and occurred more frequently in patients receiving CSA (5/5 vs. 3/11, P = 0.03). All evaluable patients developed acute GVHD; 88% had grade II-IV GVHD. Flow cytometric analysis demonstrated a substantial number of circulating CD5+ and CD3+ lymphocytes during and early after administration of XZ-CD5. These results suggest that the immunotoxin did not eliminate alloreactive T cells in this setting.

A chimeric (mouse-human) BC2 antibody (cBC2) was produced which may be used in the diagnosis and treatment of breast cancer. The BC2 variable region genes were amplified by polymerase chain reaction (PCR), using oligonucleotide primers homologous to the framework sequences of mouse VH and V kappa genes. The PCR products were used to create cBC2 expression vectors containing the mouse BC2 VH and V kappa and human constant region (IgG1 and K) genes. Chimeric antibody was produced following transfection of these constructs into Sp2/0 myeloma cells. Binding assays in vitro demonstrated that cBC2 had the same specificity for human milk fat globule membrane (HMFGM) and MUC1+ cells as mBC2, and bound antigen with a similar affinity (cBC2, Ka 5.53 +/- 2.09 x 10(8); mBC2, Ka 1.44 +/- 0.98 x 10(9)). Functionally, only cBC2 (5-25 micrograms ml-1), was able to mediate antibody-dependent cellular cytotoxicity (ADCC) with human effector cells, with 25% maximal specific lysis of MUC1+ cells at an E/T ratio of 100:1. Human complement-mediated lysis was minimal (10-15% specific lysis) with both mBC2 and cBC2. Neither cBC2 nor mBC2 was able to inhibit tumour growth in vivo in the absence of covalently coupled anticancer drugs. However, biodistribution studies demonstrated that both antibodies preferentially targeted MUC1+ tumour cells, with 17% of the injected dose of cBC2, as compared to 27% of mBC2, localized to the MUC1+ tumour at 24 h (less than 6% detected in any other tissue).