Non-invasive imaging of adaptive immunity using positron emission tomography

Summary: Non-invasive monitoring of adaptive immunity in infection, cancer, and autoimmunity remains a major challenge. Current techniques to monitor lymphocytes involve numeric and functional determinations of immune cells isolated from the peripheral blood (most often) and tissue (rarely). Invasive measurements are prone to sampling errors and are poorly reflective of the dynamic changes in the location, number, and movement of lymphoid cells. These limitations indicate the need for non-invasive whole-body imaging methodologies that allow longitudinal, quantitative, and functional analyses of the immune system in vivo . Positron emission tomography (PET), a clinically based whole-body imaging modality, has the potential to revolutionize diagnostics and therapeutic monitoring in both clinical and pre-clinical settings. This review discusses studies using PET to image adaptive immune responses in small animal models. We address the challenges inherent in assessing whole-body immunity with PET and recent developments that can improve its performance. Finally, we discuss work to translate PET immune imaging into clinical practice.     

Simple procedure for assessing relative quantities of neutral and acidic sugars in mucin glycoproteins: its use in assessing cyclical changes in cervical mucins.

A simple histochemical procedure for assessing relative amounts of neutral and acidic sugars in mucin glycoproteins, and its application in the study of cyclical changes of human cervical mucins, is described. This procedure, the saponification/selective periodate oxidation/borohydride reduction/alcian blue pH 2.5/periodic acid Schiff (KOH/PA*/Bh/Ab 2.5/PAS) method, uses a selective oxidation step to remove the PAS positivity of sialic acid; thus only neutral sugars stain positively with PAS, and acidic sugars (O-sulphate esters and carboxyl groups) stain with alcian blue. This differs from the KOH/Ab/PAS technique which stains sialic acid residues with both alcian blue and PAS. Applying the KOH/PA*/Bh/Ab 2.5/PAS technique to the study of cyclical changes of human cervical mucins, a decreased neutral:acidic sugar ratio in the secretory phase mucins compared with those of the proliferative phase was found. This difference was not seen with KOH/Ab/PAS staining in the same cases. The techniques and reagents used in this procedure can be easily applied in a clinical histopathology laboratory.     

Hair sampling for chromium content following Charnley hip arthroplasty.

The chromium content of hair has been studied by neutron activation analysis of samples from 62 patients following a Charnley unilateral or bilateral hip arthroplasty by an artificial joint of stainless steel against polyethylene, inserted three to five years previously. The patients lived in the North Wales area of the British Isles. Hair chromium content was also studied in 51 control subjects of similar age to that of the patients, from the same geographical area and often from the patients' own households. Chromium content was recorded as parts per million (ppm) of hair weighed and analyzed in the state received, without preliminary ashing or chemical "washing" of the samples in the laboratory. Fifty of the 51 control subjects showed less than 2 ppm chromium in hair; one showed 2-5 ppm; none showed more than 5 ppm. Fifty-nine of the 62 patients showed less than 2 ppm chromium in hair; three showed 2-5 ppm; none showed more than 5 ppm. Attention is drawn to certain practical aspects when collecting hair samples for chromium analysis. The use and validity of hair sampling as one method of screening for systemic chromium accumulation following implant surgery is discussed. The method may be a useful adjunct to monitoring of chromium levels in blood samples. In this preliminary study, hair sampling has given no evidence of any major risk of systemic chromium accumulation in patients using a Charnley arthroplasty for periods of up to five years; no conclusion can be made concerning periods longer than this. The findings do not exclude systemic reactions of the hypersensitivity type, since this type of reaction could develop to only small amounts of chromium.     

Detection of clonal immunoglobulin gene rearrangements in the peripheral blood progenitor cells of patients with multiple myeloma: the potential role of purging with CD34 positive selection

Aims—To determine the extent of clonal cell contamination of peripheral blood progenitor cell (PBPC) collections in patients with multiple myeloma (MM) and to assess the purging efficacy of CD34 positive selection.     

No evidence that common allelic variation in the Amyloid Precursor Protein (APP) gene confers susceptibility to Alzheimer's disease

In order to test the hypothesis that allelic variation withinthe Amyloid Precursor Protein (APP) gene influences susceptibilityto common forms of Alzheimer's disease (AD) we screened theentire coding, promoter and 3' untranslated sequences of theAPP gene for DNA variations in 30 unrelated patIents and eightcontrols with probable AD by a combination of RT-PCR, PCR andchemical cleavage mismatch analysis. Although we were unableto detect commonly occurring allelic variants, we were ableto detect a novel mutation within the APP gene in one individualwith late-onset AD. This mutation resulted in the substitutionof a tryptophan residue for an arginine residue at codon 328wIthin exon 7 which encodes the so-called protease Inhibitordomain of the 751 residue APP Isoform. However, the pathologicalsignificance of this mutation is uncertain as neither this,nor any other mutation occurring within exon 7 of the APP genewas found in any of a further 102 AD patients and 86 age-matchedcontrols. In conclusion, it is unlikely that susceptibilityto AD results from commonly occurring allelic variants of theAPP gene and it is even less probable that mutations withinexon 7 of the APP gene are important risk factors for late-onsetAD.     

Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the {alpha}1 subunit of the inhibitory glycine receptor

Startle disease, or hyperekplexia, is characterized by an exaggeratedstartle reflex and neonatal hypertonla. An autosomal dominantform of the disorder Is associated with mutations In the samecodon of the ¹ subunit of the inhibitory glycine receptor (GLRA1) resulting in the substitution of an uncharged amlno acidfor Arg271 in the mature protein. However, recessive transmissionIs seen in the mouse mutant spasmodic which resembles startledisease phenotypcially and is also associated with mutationsIn Glra 1. We have confirmed the finding of Arg271 mutationsIn individuals with startle disease in a UK family showing autosomaldominant transmission. In addition we describe an apparentlysporadic case, the offspring of a consanguineous mating, whoIs homozygous for a novel mutation (T1112A) in GLRA 1, whichresults In the substitution of asparagine for isoleucine atposition 244 of the mature protein. This suggests that humanstartle disease can display recessive as well as dominant inheritanceresulting from different mutations in GLRA 1.     

Prevention of immunoglobulin production by allotype-dependent T cells.

Adoptive lymphocyte transfers between Iga, Igb and Igd allotype-congenic mouse strains revealed host barriers against the production of certain donor allotypes. First, as recipients of Igb cells, Iga and Igd mice permitted the production of donor Ig-4b but not that of Ig-1 b. The apparent mediators of this Ig-1 b barrier were T cells specific for Ig- 1 b determinants on B cells. Additional cell transfers showed Iga mice to have a second barrier against allotype production by Igd donor cells. Reciprocal cell transfers showed Igb and Igd mice to have comparatively weak barriers against Iga-producing cells. As host barriers were absent in mice deficient for T cells (athymic nude mice), it appears that they are T cell-mediated. Further, the allotype-dependence of such barriers means that the antigens responsible must be under the control of allotype-linked genes. The regulatory implications of this for the immune system are discussed.