Preimplantation factor (PIF) is a novel embryo-secreted immunomodulatory peptide. Its synthetic analog (sPIF) modulates maternal immunity without suppression. There is an urgent need to develop agents that could prevent the development of type 1 diabetes mellitus (TIDM). Herein, we examine sPIF's preventive effect on TIDM development by using acute adoptive-transfer (ATDM) and spontaneously developing (SDM) in non-obese diabetic (NOD) murine models. Diabetes was evaluated by urinary and plasma glucose, intraperitoneal glucose tolerance test (IPGTT), pancreatic islets insulin staining by immunohistochemistry and by pancreatic proteome evaluation using mass spectrometry, followed by signal pathway analysis. Continuous administration of sPIF for 4-weeks prevents diabetes development in ATDM model in >90% of recipients demonstrated by normal IPGTT, preserved islets architecture, number, and insulin staining. (P < 0.01). sPIF effect was specific; its protective effects are not replicated by scrambled PIF (χ(2) = 0.009) control. sPIF led also to increased circulating Th2 and Th1 cytokines. In SDM model, 4-week continuous sPIF administration prevented onset of diabetes for 21 weeks post-therapy (P < 0.01). Low-dose sPIF administration for 16 weeks prevented diabetes development up to 14 weeks post-therapy, evidenced by preserved islets architecture and insulin staining. In SDM model, pancreatic proteome pathway analysis demonstrated that sPIF regulates protein traffic, prevents protein misfolding and aggregation, and reduces oxidative stress and islets apoptosis, leading to preserved insulin staining. sPIF further increased insulin receptor expression and reduced actin and tubulin proteins, thereby blocking neutrophil invasion and inflammation. Exocrine pancreatic function was also preserved. sPIF administration results in marked prevention of spontaneous and induced adoptive-transfer diabetes suggesting its potential effectiveness in treating early-stage TIDM.
BackgroundDespite chemo-induction therapy and autologous stem cell transplantation (ASCT), the vast majority of patients with Multiple Myeloma (MM) relapse within 7 years and the disease remains incurable. Adoptive Allogeneic T-cell therapy (ATCT) might be curative for MM, however current ATCT protocols often lead to graft versus host disease (GvHD). Transplanting only tumor reactive donor T cells that mediate a graft-versus-myeloma (GvM) but not GvHD may overcome this problem.MethodsWe used an MHC-matched/miHA-disparate B10.D2 → Balb/c bone marrow transplantation (BMT) murine model and MOPC315.BM MM cells to develop an ATCT protocol consisting of total body irradiation, autologous-BMT and infusion of selective, myeloma-reactive lymphocytes of T cell receptor (TCR) Vβ 2, 3 and 8.3 families (MM-auto BMT ATCT).ResultsPre-stimulation ex vivo of allogeneic T cells by exposure to MOPC315.BM MM cells in the presence of IL-2, anti-CD3 and anti-CD28 resulted in expansion of the myeloma-reactive T cell TCRVβ 2, 3 and 8.3 subfamilies. Their isolation and infusion into MM-bearing mice resulted in a vigorous GvM response without induction GvHD and long-term survival. Repeated infusion of naïve myeloma-reactive T cell TCRVβ 2, 3 and 8.3 subfamilies was also effective.ConclusionsThese data demonstrate that a transplantation protocol involving only selective tumor-reactive donor T cell families is an effective immunotherapy and results in long-term survival in a mouse model of human MM. The results highlight the need to develop similar ATCT strategies for MM patients that result in enhanced survival without symptoms of GvHD.
Donor lymphocyte infusion (DLI) is a powerful immune-manipulation for the induction of Graft-vs-Leukemia (GVL) effect, but it is associated with high incidence of Graft-vs-host disease (GVHD). Furthermore, the use of DLI across MHC mismatched transplantation is almost infeasible. Extra corporal photochemotherapy for the treatment of GVHD involves extra corporal exposure of peripheral blood mononuclear cells to photoactivated 8-methoxypsorelen (8-MOP) followed by re-infusion of the treated cells. Based on the immunomodulatory effects of 8-MOP and UVA irradiation we investigated ex-vivo similar treatment of donor cells prior to cell therapy in post-transplant murine model. F1 leukemic (BCL1) recipients exposed to total body irradiation followed by bone marrow transplantation (BMT) (C57BL/6→F1). Donor splenocytes incubated with 8-MOP and 10 minuets exposure to UVA irradiation were administrated twice a week for the first 21 days post-BMT. Irradiated hosts inoculated with BCL1 and C57BL/6 cells were examined for the presence of donor cells using fluorescence-activated cell sorting analysis. At 4–6 weeks after BMT chimerism analysis revealed a ratio of 84–91% donor cells. Murine blood cells were tested for Minimal residual disease (MRD) by BCL1- specific PCR for detection of dormant BCL1 at 2 months after BMT. In comparison with the control group, DLI with ex vivo 8-MOP UVA treated splenocytes reduced GVHD and retained GVL effect. In vitro secretion of interferon gamma by treated cells was reduced only by 50%. Clinical application of this method was performed in 4 high-risk patients after stem cell transplantation from haploidentical related donors: GVHD T-Cell Dose Day post HSCT Disease UPN - 105/kg +175 Refractory HD+CMV disease #1935 - 104/kg 105/kg +70 +90 Metastatic testicular Ca. #2255 - 5×105/kg 106/kg +84 +127 Refractory neuroblastoma #2316 - 105/kg +130 Relapsed ALL #2323 The potential of Ex-Vivo 8-MOP UVA DLI treated cells should further be investigated for induction of GVL w/o GVHD, to improve chimerism and for anti viral therapy (CMV, EBV and PTLD - Post Transplant Lymphoproliferative Disorders)
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