Are soluble monocyte-derived HLA class II molecules candidates for immunosuppressive activity?

Claus, Renate; Werner, H.; Schulze, Hans-Arthur; Walzel, Hermann; Friemel, H

doi:10.1016/0165-2478(90)90147-i

Cited by 25 publications

(9 citation statements)

References 39 publications

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“…Because of the chronic treatment with factor VIII preparations, the contaminating sHLA mole cules may exert immunomodulating effects, e.g. by inter fering will the T-cell receptor [14,15] and the accessory membrane ligands CD4 or CD8. This could explain the as sociation between the purity of these concentrates and CD4+ cell counts in treated AIDS patients, as recently re ported by Hilgartner et al [4], Similarly, Serementis et al [5] and Vermylen and Briet [6] described a strikingly slower decline of CD4+ lymphocyte counts in HIV-seropositive haemophiliacs treated with MAB purified products.…”

Section: Resultsmentioning

confidence: 99%

Soluble HLA Class I and Class II Concentrations in Factor VIII and PCC Preparations

Westhoff¹,

Grosse‐Wilde²

1995

Vox Sanguinis

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Soluble HLA class 1 (sHLA-CI) and class II (sHLA-CII) molecules were quantitated in 11 commercially available factor VIII and prothrombin complex concentrate (PCC) preparations by enzyme-linked immunosorbent assays (ELISA). In 4 preparations, we detected traces of sHLA-CI (0.01-0.07 mg/l), and in 7 hemostatic preparations small amounts of sHLA-CII molecules (0.02-0.28 mg/l). The concentrations of these contaminant molecules are unequivocally below the mean values of sHLA in human plasma (sHLA-CI: 1.01±0.72 mg/l; sHLA-CII: 1.53±2.44 mg/l). Based on the total amount of chronically administered factor VIII or PCC, contaminating sHLA molecules may be in principle able to exert immunomodulatory effects in patients treated with such preparations.

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Section: Resultsmentioning

confidence: 99%

Soluble HLA Class I and Class II Concentrations in Factor VIII and PCC Preparations

Westhoff¹,

Grosse‐Wilde²

1995

Vox Sanguinis

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“…Soluble human leukocyte antigen (HLA) class I and II molecules are present in some IVIG products, as are their “physiological ligands,” CD4 and CD8 [65,66]. Soluble CD4 in IVIG might interfere with HLA class II molecules on antigen-presenting cells, competing with HLA-class II-restricted T cells and possibly causing immunosuppression [66,67]. Transforming growth factor (TGF)-β1 and TGF-β2 are also present in IVIG [68].…”

Section: Considerations Relating To Treatment Of Ad With Ivig Productsmentioning

confidence: 99%

Intravenous immunoglobulin and Alzheimer’s disease: what now?

Loeffler

2013

J Neuroinflammation

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Intravenous immunoglobulin (IVIG) products are prepared from purified plasma immunoglobulins from large numbers of healthy donors. Pilot studies with the IVIG preparations Octagam and Gammagard in individuals with mild-to-moderate Alzheimer’s disease (AD) suggested stabilization of cognitive functioning in these patients, and a phase II trial with Gammagard reported similar findings. However, subsequent reports from Octagam’s phase II trial and Gammagard’s phase III trial found no evidence for slowing of AD progression. Although these recent disappointing results have reduced enthusiasm for IVIG as a possible treatment for AD, it is premature to draw final conclusions; a phase III AD trial with the IVIG product Flebogamma is still in progress. IVIG was the first attempt to use multiple antibodies to treat AD. This approach should be preferable to administration of single monoclonal antibodies in view of the multiple processes that are thought to contribute to AD neuropathology. Development of “AD-specific” preparations with higher concentrations of selected human antibodies and perhaps modified in other ways (such as increasing their anti-inflammatory effects and/or ability to cross the blood–brain barrier) should be considered. Such preparations, if generated with recombinant technology, could overcome the problems of high cost and limited supplies, which have been major concerns relating to the possible widespread use of IVIG in AD patients. This review summarizes the recent AD IVIG trials and discusses the major issues relating to possible use of IVIG for treating AD, as well as the critical questions which remain.

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“…Therefore this allows a means to specifically regulate PI 3-kinase inside cells. If higher concentrations are used it would inhibit PI 3-kinase activity, and this could be used as a basis of immunosuppressive therapy (5,22) or potentially as a basis for antitumor therapy (23). There is evidence that soluble MHC molecules circulate in the serum (22,24,25), so it is possible that such a mechanism may even have localized functional significance for PI 3-kinase regulation in vivo.…”

Section: Figmentioning

confidence: 99%

“…If higher concentrations are used it would inhibit PI 3-kinase activity, and this could be used as a basis of immunosuppressive therapy (5,22) or potentially as a basis for antitumor therapy (23). There is evidence that soluble MHC molecules circulate in the serum (22,24,25), so it is possible that such a mechanism may even have localized functional significance for PI 3-kinase regulation in vivo. As a research tool the peptides may be also useful in dissecting the specific contribution of class Ia PI 3-kinase in several signaling pathways as using these allows specific activation of PI 3-kinase-dependent signaling pathways and allows investigation of these in isolation from the other pathways that would inevitably be activated by, for example, growth factor stimulation of cells.…”

Section: Figmentioning

confidence: 99%

Direct Interaction of Major Histocompatibility Complex Class II-derived Peptides with Class Ia Phosphoinositide 3-Kinase Results in Dose-dependent Stimulatory Effects

Foukas

Panayotou

Shepherd

2004

Journal of Biological Chemistry

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Peptides corresponding to residues 65-79 of human lymphocyte antigen class II sequence (DQA*03011) are cell-permeable and at high concentrations block activation of protein kinase B/Akt and p70-S6 kinase in T-cells, effects attributed to inhibition of phosphoinositide (PI) 3-kinase activity. To understand the molecular basis of this, we analyzed the effect this peptide had on activity of class I PI 3-kinases. Although there was no effect on the activity of class Ib PI 3-kinase or on the protein kinase activity of class I PI 3-kinases, there was a biphasic effect on lipid kinase activity of the class Ia enzymes. There was an inhibition of activity at higher peptide concentrations because of a formation of insoluble complexes between peptide and enzyme. Conversely, at lower peptide concentrations there was a profound activation of PI 3-kinase activity of class Ia PI 3-kinases. Studies of peptide variants revealed that all active peptides conform to heptad repeat motifs characteristic of coiled-coil helices. Surface plasmon resonance studies confirmed direct sequence-specific binding of active peptide to the p85␣ adapter subunit of class Ia PI 3-kinase. Active peptides also activated protein kinase B and extracellular signal-regulated kinase (ERK) in vivo in a wortmannin-sensitive manner while reducing recoverable cellular p85 levels. These results indicate that the human lymphocyte antigen class II-derived peptides regulate PI 3-kinase by direct interaction, probably via the coiled-coil domain. These peptides define a novel mechanism of regulating PI 3-kinase and will provide a useful tool for specifically dissecting the function of class Ia PI 3-kinase in cells and for probing structurefunction relationships in the class Ia PI 3-kinase heterodimers. Phosphoinositide (PI)1 3-kinases play a pivotal role in signaling pathways regulating a wide range of cellular processes including apoptosis, metabolism, cell growth, cell proliferation, and cytoskeletal rearrangements (1-3). Several classes of PI 3-kinase exist, but tyrosine kinase-linked receptors signal mainly through class Ia PI 3-kinases, which are bifunctional kinases, possessing both lipid and protein kinase activities (4). The class Ia PI 3-kinases can be regulated in a number of ways. These include interactions via the SH2, SH3, and Bcr homology domains of the adapter subunit and direct interaction of Ras through the Ras binding domain of the catalytic subunit (1-3).A potentially novel mechanism for regulating PI 3-kinase activity has recently emerged from studies of the properties of biologically active peptides derived from class II MHC molecules (5). These studies identified a peptide fragment of DQA*03011 ␣ chain allele of MHC class II that was capable of blocking IL2-induced T-cell proliferation and thus offered a possibly novel means of achieving immunosuppression. Further work found that treatment of T-cells with one of these peptides, corresponding to the residues 65-79 of DQA*03011, blocked IL2-induced activation of protein kinase B/Akt and p70-S6K a...

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Are soluble monocyte-derived HLA class II molecules candidates for immunosuppressive activity?

Cited by 25 publications

References 39 publications

Soluble HLA Class I and Class II Concentrations in Factor VIII and PCC Preparations

Soluble HLA Class I and Class II Concentrations in Factor VIII and PCC Preparations

Intravenous immunoglobulin and Alzheimer’s disease: what now?

Direct Interaction of Major Histocompatibility Complex Class II-derived Peptides with Class Ia Phosphoinositide 3-Kinase Results in Dose-dependent Stimulatory Effects

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