Norbert Ahrens

Mycophenolate-mofetil in the treatment of refractory multiple sclerosis.

Sirs: Multiple sclerosis (MS) is thought to be an autoimmune disease stimulated by activated lymphocytes, and the entry of T and B cells into the central nervous system [1]. Despite the use of a variety of immunomodulatory and immunosuppressive agents including interferon beta, glatiramer acetate, intravenous immunoglobulins, azathioprine and escalating chemotherapy with mitoxantrone and cyclophosphamide, MS remains progressive in a large number of patients and there is an ongoing need for further rescue therapy [2, 3]. Mycophenolate-mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase, which is necessary for de novo purine biosynthesis in lymphocytes. The drug is being successfully and increasingly used for prevention of organ transplant rejection [4]. Beneficial effects in the treatment of autoimmune diseases have been shown in Crohn’s disease [5]. The inhibition of lymphocytes by the drug may therefore result in improvement in patients with refractory MS. In this open surveillance trial, we treated seven patients with chronic progressive or relapsing MS (table). The patients were informed about the drug and its attendant risks, and all gave informed consent before initiation of treatment. Entry criteria in this trial included the diagnosis of MS, disease-progression in terms of EDSS despite established treatment (table), and no other diseases such as infections or liver or kidney disorders. All patients received the usual dose employed in the treatment of transplanted patients (2 g per day). The administration of MMF led to improvement or stopped progression in five cases (table). Three of the five patients emphasized improved movement, although EDSS did not change. One of the five patients (no. 7) had to reduce the dose from 2 to 1.5 gr per day because of frequent infections, one (no. 2) discontinued the treatment owing to uncontrolled nausea. Two patients without beneficial effects stopped the drug through nausea and/or non-response (nos. 3 and 5). MRI findings before and at least 6 months after treatment start were available in two patients (no. 1 and 7) and showed fewer lesions and no change, respectively. The four patients, who still receive MMF, are feeling well without progression and would like to continue this therapy. In all seven treated patients there was no deterioration concerning EDSS. Although the beneficial effects in five patients demonstrate that MMF may be of value in the treatment of MS, this open-label study does not allow a final conclusion. The question of whether more responsive patients would be found in an unselected group requires further study. LETTER TO THE EDITORS

Coexistence of autoantibodies and alloantibodies to red blood cells due to blood transfusion.

BACKGROUND: Autoantibodies (AUTO) to red blood cells (RBCs) are frequently associated with alloantibodies (ALLO). The mechanism for the coexistence of these antibodies is obscure.

Oxaliplatin‐induced immune pancytopenia

BACKGROUND: Oxaliplatin, a third‐generation platinum compound, has been implicated in isolated cases of immune hemolytic anemia and/or immune thrombocytopenia. The first case of severe immune pancytopenia related to oxaliplatin is described.

Genetic diversity of KELnull and KELel: a nationwide Austrian survey

BACKGROUND: Besides ABO and RH, the KEL blood group system, including the two antithetical antigens KEL1 and KEL2, is the most important owing to the frequent appearance of anti‐KEL alloantibodies and their considerable clinical significance. So far, only limited information was available on KEL variant alleles determining the rare silent KELnull and KELel phenotypes with absent or diminished KEL antigen expression detected only by adsorption‐elution techniques, respectively.

Laser Ablation–Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Detecting Rare Cells in Tissue Sections

Administering immunoregulatory cells to patients as medicinal agents is a potentially revolutionary approach to the treatment of immunologically mediated diseases. Presently, there are no satisfactory, clinically applicable methods of tracking human cells in patients with adequate spatial resolution and target cell specificity over a sufficient period of time. Laser ablation–inductively coupled plasma mass spectrometry (LA-ICP-MS) represents a potential solution to the problem of detecting very rare cells in tissues. In this article, this exquisitely sensitive technique is applied to the tracking of gold-labeled human regulatory macrophages (Mregs) in immunodeficient mice. Optimal conditions for labeling Mregs with 50-nm gold particles were investigated by exposing Mregs in culture to variable concentrations of label: Mregs incubated with 3.5 × 109 particles/ml for 1 h incorporated an average of 3.39 × 108 Au atoms/cell without loss of cell viability. Analysis of single, gold-labeled Mregs by LA-ICP-MS registered an average of 1.9 × 105 counts/cell. Under these conditions, 100% labeling efficiency was achieved, and label was retained by Mregs for ≥36 h. Gold-labeled Mregs adhered to glass surfaces; after 24 h of culture, it was possible to colabel these cells with human-specific 154Sm-tagged anti–HLA-DR or 174Yb-tagged anti-CD45 mAbs. Following injection into immunodeficient mice, signals from gold-labeled human Mregs could be detected in mouse lung, liver, and spleen for at least 7 d by solution-based inductively coupled plasma mass spectrometry and LA-ICP-MS. These promising results indicate that LA-ICP-MS tissue imaging has great potential as an analytical technique in immunology.

First-in-Human Case Study: Multipotent Adult Progenitor Cells for Immunomodulation After Liver Transplantation

Mesenchymal stem cells and multipotent adult progenitor cells (MAPCs) have been proposed as novel therapeutics for solid organ transplant recipients with the aim of reducing exposure to pharmacological immunosuppression and its side effects. In the present study, we describe the clinical course of the first patient of the phase I, dose‐escalation safety and feasibility study, MiSOT‐I (Mesenchymal Stem Cells in Solid Organ Transplantation Phase I). After receiving a living‐related liver graft, the patient was given one intraportal injection and one intravenous infusion of third‐party MAPC in a low‐dose pharmacological immunosuppressive background. Cell administration was found to be technically feasible; importantly, we found no evidence of acute toxicity associated with MAPC infusions.

Comparison of two leukapheresis programs for computerized collection of blood progenitor cells on a new cell separator

BACKGROUND : Peripheral blood progenitor cells (PBPCs) can be collected on various cell separators. Two leukapheresis programs (LP‐MNC and LP‐PBSC‐Lym) were evaluated for computerized collection of PBPCs on a new cell separator.

Association between alloantibody specificity and autoantibodies to red blood cells

BACKGROUND: Alloantibodies (ALLOs) to red blood cells (RBCs) are frequently associated with autoantibodies (AABs). An association between ALLO specificity and AABs has not yet been described.

Clinical management of patients receiving cell-based immunoregulatory therapy

Administering immunoregulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain‐of‐function antigen‐specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell‐based immunotherapy, focusing on treatment of renal transplant recipients with regulatory macrophages as a concrete example.

In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.