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This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies., (© 2022. The Author(s).)

Aging is associated with the impairment of stem cell activation, leading to the functional decline of tissues and increasing the risk for age-associated diseases. The old, damaged or unrepaired tissues disturb distant tissue homeostasis by secreting factors into the circulation, which may not only serve as biomarkers for specific age-associated pathologies but also induce a variety of degenerative phenotypes. In this review, we summarize and discuss systemic determinants that perpetuate age-related tissue dysfunction. We further elaborate on the effects of attenuating these circulating factors by highlighting recent advances which utilize plasmapheresis in a pre-clinical or clinical setting. Overall, we postulate that repositioning therapeutic plasma exchange (TPE) to dilute the systemic factors, which become deleterious at their age-elevated levels, could be a rapidly effective rejuvenation therapy that recalibrates crucial signaling pathways to a youthful state., (Copyright © 2021. Published by Elsevier Ltd.)

The population of baby boomers (age 60-65) is rapidly increasing globally. The aging of the human body is associated with the decline of cellular function which leads to the development of a variety of diseases. The increased demand for health care for the aging population creates significant financial burden to any healthcare system. Developing strategies and health intervention methods to ameliorate this situation is paramount. Experiments utilizing heterochronic parabiosis in mice have demonstrated that replacing the aging cellular milieu with the plasma of a young experimental animal leads to reversal of cellular senescence. This article describes a hypothetical model of intermittent heterochronic plasma exchange in humans as a modality for heterochronic parabiosis in an attempt to delay cellular senescence., (Copyright © 2013 Wiley Periodicals, Inc.)

One of the most common uses of therapeutic plasmapheresis is for the treatment of immunologically mediated polyneuropathies. This paper discusses the use of plasmapheresis in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, polyneuropathies associated with paraproteins, lower motor neuron syndromes, and polyneuropathies associated with HIV. As the pathogenesis of immunologically mediated polyneuropathies becomes better understood, newer therapies for these syndromes will evolve: however, therapeutic plasmapheresis is likely to continue to play a central role in the treatment of many of these diseases.

In order to evaluate the nature and frequency of adverse reactions associated with Therapeutic Apheresis (TA), database information from two large mobile apheresis services was analyzed. A total of 17,940 procedures performed on 3,583 patients were studied using an Access Database. Seventy percent (12,558) of the procedures were performed on a Fresenius AS104 blood cell separator and 30% (5,382) were performed on a COBE Spectra. The five most commonly treated diseases were Guillain-Barre Syndrome (25%), thrombotic thrombocytopenic purpura (20%), myasthenia gravis (18%), the hyperviscosity syndrome (12%), and chronic inflammatory demyelinating polyneuropathy (9%). All patients received calcium gluconate supplement during the procedures. Cardiac monitoring was used during 80% of the procedures and blood pressure monitoring was used during all procedures. All procedures were supervised by a physician. Both apheresis services fully comply with the ASFA Guidelines for Therapeutic Apheresis Providers. Adverse reactions occurred in 3.9% of all procedures. The following adverse reactions were documented: reactions related to ACD toxicity (3%), vasovagal reactions (0.5%), vascular access related complications (0.15%), reactions related to FFP (0.12%), hepatitis B from FFP (0.06%), arrhythmias (0.01%), hemolysis due to inappropriate dilution of 25% albumin (0.01%), and one death (from underlying disease) during a TA procedure (0.006%). These data demonstrate that therapeutic apheresis is associated with a low rate of side effects when performed by well-trained and certified nurses under the direction of experienced physicians, even in the diverse setting of large mobile therapeutic apheresis programs., (Copyright 2001 Wiley-Liss, Inc.)

Problem: Several studies have evaluated the effect of intravenous gammaglobulin (IVIG) in women with unexplained recurrent spontaneous abortions (RSA). Data regarding the underlying immunologic abnormalities in these patients is scant. This study reports the pregnancy outcome and immunologic changes observed in a large group of women with RSA associated with well-defined alloimmune and autoimmune abnormalities treated with IVIG., Methods: Thirty-five patients with three or more recurrent miscarriages were studied. None of the patients had identifiable alloimmune response to paternal lymphocytes. Twenty-four patients had anti-thyroid antibodies, ten patients had high levels of circulating immune complexes, and six patients had anti-cardiolipin antibodies. Five patients had Hashimoto's disease, one had immune thrombocytopenic purpura, and one had Crohn's disease. Twenty-three patients had more than one autoimmune abnormality. All patients received IVIG infusions (200-250 mg/kg) every 3 weeks during the first 8 months of pregnancy., Results: Twenty-eight patients (80%) had a successful pregnancy. Decrease of the level of autoantibodies and circulating immune complexes was observed in all patients who had a successful pregnancy. Only three of these patients developed measurable alloimmune response to paternal antigens., Conclusions: This preliminary study suggests that IVIG may be of benefit to patients with recurrent pregnancy associated with combined alloimmune and autoimmune abnormalities. This benefit was seen in spite of lack of detectable correction of the alloimmune abnormality in the majority of patients.

Therapeutic use of interferon-alpha (IFN-alpha) has been associated with the development of a variety of autoimmune disorders. We describe a patient who received chronic treatment with IFN-alpha following autologous bone marrow transplantation for multiple myeloma. The patient developed an antibody inhibitor directed against factor VIII coagulant protein (FVIIIC) leading to a fatal hemorrhagic diathesis. The association between IFN-alpha therapy and autoimmune complications deserves wider recognition and further study.

Myasthenic crisis is a potentially life-threatening complication of myasthenia gravis that requires aggressive therapy. We describe four patients in whom myasthenic crisis developed and who failed to respond to initial treatment with intravenous gamma-globulin. All four patients subsequently responded to intensive plasma exchange. Based on our experience, plasmapheresis appears to be superior to intravenous gamma-globulin for the treatment of myasthenic crisis in certain patients. Prognostic factors that determine the effectiveness of intravenous gamma-globulin vs plasmapheresis in these patients merit further investigation.

Dendritic cells, the primary antigen presenting cells of the human immune system, are heavily infected with human immunodeficiency virus (HIV) in patients with the acquired immunodeficiency syndrome (AIDS). Dinitrochlorobenzene (DNCB) is a contact sensitizing agent that acts as a potent immune modulator of dendritic cells. In this pilot study, we examined the safety and efficacy of topical DNCB application in patients with early HIV disease. Topical DNCB was well tolerated by these patients, with an adverse reaction rate of 10%. CD4+ T-cell counts remained stable with repeated DNCB use. In contrast, CD8+ T-cell counts and natural killer cells increased significantly following DNCB sensitization. This increase in CD8+ T-cell and natural killer cell subsets was accompanied by a decrease in HIV replication, as measured by serum HIV RNA levels. Based on this pilot study, we conclude that topical DNCB is safe in early HIV disease and may decrease viral load via a systemic effect on dendritic cells, CD8+ T-cells and natural killer cells. These results require confirmation in larger controlled trials.

We describe a patient with human immunodeficiency virus (HIV) infection who developed mononeuritis multiplex associated with polyclonal (type III) cryoglobulinemia. The patient's symptoms stabilized following treatment with plasmapheresis and removal of the cryoglobulin. Our case represents the first report of polyclonal cryoglobulinemia in HIV disease and suggests that cryoglobulinemia may play an etiologic role in some patients with HIV-associated neuropathy.

Although thrombotic thrombocytopenic purpura (TTP) has been described in patients with systemic lupus erythematosus (SLE), the relationship between these 2 diseases is controversial. We recently treated a patient with longstanding SLE who developed TTP. The patient responded to therapy with aggressive plasmapheresis. Review of the literature revealed that TTP may occur in the setting of either active or inactive SLE. Survival in SLE associated TTP correlated with the use of plasma therapy (plasma infusion or plasmapheresis) rather than with the activity of the underlying autoimmune disease. We conclude that TTP and SLE represent distinct clinical entities that may occur together in an immunologically predisposed host. The use of plasma therapy appears to have had a significant impact on survival in these patients.

In their severest forms, pre-eclampsia and eclampsia may be life-threatening complications of pregnancy. We describe a patient with severe post-partum eclampsia characterized by seizures, deep coma, hypertension, renal insufficiency, coagulopathy, and microangiopathic hemolysis. The patient responded to treatment that included intensive plasma exchange, and she achieved full recovery. Our case supports the use of plasma exchange in patients with severe pre-eclampsia and eclampsia.

Acute disseminated encephalomyelitis (ADEM) is a demyelinating central nervous system disease that is associated with high morbidity and mortality. Although the recognition of ADEM may be facilitated by newer imaging techniques, the optimal treatment of this disease remains uncertain. We describe 4 patients with severe ADEM who responded to treatment that included intensive plasmapheresis. Two of the patients were in coma at the time that plasmapheresis was instituted, and all 4 patients made an excellent recovery. Immunologic studies revealed increased serum IgA levels, increased circulating immune complex levels as measured by the Raji cell assay, and decreased numbers of T and B cells prior to treatment of ADEM. These abnormalities improved following plasma exchange. Plasmapheresis appears to be effective in reversing the neuropathologic process in ADEM. The role of this treatment modality in ADEM requires further evaluation in controlled clinical trials.

Thirty-seven HIV-infected homosexual men with thrombocytopenia (less than 100 x 10(9)/l) received protein A immunoadsorption treatments to remove platelet-sensitizing immunoglobulin (Ig) G and circulating immune complexes (CIC) from plasma. Patients received an average of six treatments each, consisting of 250 ml plasma over a 3-week period. Clinical improvement in hemorrhagic symptoms associated with substantial increase in platelet counts was achieved in 18 patients. These responses were maintained over a median follow-up period of more than 7 months in 14 evaluable patients who were not lost to follow-up (three patients relapsed in 2 weeks and one received another therapy). Generally, moderate transient treatment-related side-effects included fever, musculoskeletal pain, chills and nausea. A transient serum sickness-like reaction was observed in seven patients, leading to termination of treatment in two. Clinical responses were associated with significant decreases in levels of platelet-sensitizing Ig, including CIC. Stimulation of broadly cross-reactive anti-antigen-binding fragment [F(ab)2], antibodies contributed to these responses. Protein A immunoadsorption is an effective alternative treatment for HIV-associated thrombocytopenia.

Three patients presented with gradual onset of proximal muscle weakness. Electromyography and muscle biopsy were abnormal in each patient and typical of myositis. All three had an IgG kappa monoclonal paraprotein in the serum. Examination of muscle biopsy specimens by direct immunofluorescence revealed linear deposits of IgG kappa along the sarcolemmal basement membrane of individual fibres. Stains for lambda light chains, other immunoglobulins, and complement components were negative. Plasmapheresis and immunosuppressive drugs produced clinical improvement in all three patients. Muscle biopsies were taken from two of the patients after plasma exchange and drug therapy and showed no immune deposits. These observations suggest a possible cause-and-effect relation between the serum paraprotein and the inflammatory myopathy in these patients.

The removal of immune complexes, autoantibodies and suppressor factors from the circulation of patients with AIDS and AIDS related conditions by plasmapheresis and selective immunoadsorption may play a role as a therapeutic modality in these disorders. Lymphocytapheresis may also be of potential use in AIDS related conditions with presumed autoimmune basis. Perfusion of plasma over immobilized protein A columns is being evaluated as a possible immunomodulatory and antitumor therapy in patients with AIDS related Kaposi's sarcoma. Although apheresis procedures as a therapeutic modality in AIDS related conditions are still at the experimental stage, preliminary results are encouraging. The possible transmission of the disease by blood products presents a health hazard to health workers involved in the field of apheresis. Since the mode of transmission of the disease appears to be similar to hepatitis B, strict hepatitis B precautions should be enforced in every case in which AIDS suspected blood is being processed.

Circulating immune complexes, autoantibodies, and suppressor factors to normal lymphoproliferation may play an important role in the induction and maintenance of the cellular immunodeficiency characteristic for the acquired immunodeficiency syndrome (AIDS) and its related conditions. In order to explore the possibility that the removal of circulating humoral factors may have an immunomodulatory effect in patients with AIDS and AIDS-related conditions (ARC), we used apheresis procedures to treat patients with different clinical presentations of AIDS and ARC. Five patients with AIDS and opportunistic infections were treated with plasmapheresis. Four patients with AIDS and Kaposi's sarcoma without opportunistic infections were treated with staph protein-A immunoadsorption and two patients with ARC and peripheral neuropathy were treated with lymphoplasmapheresis. The treatments were tolerated well by all patients. Effective removal of circulating humoral immune factors was observed in all three groups. No significant clinical benefit was seen in the patients with AIDS and opportunistic infections treated with plasmapheresis. Partial tumor responses were observed in three of the four patients with AIDS related Kaposi's sarcoma treated with staph protein-A plasma perfusion, and resolution of neurologic symptoms was seen in both patients with ARC and peripheral neuropathy treated with lymphoplasmapheresis. Our preliminary results suggest that lymphoplasmapheresis may be an effective treatment modality for patients with ARC related peripheral neuropathy, that protein-A immunoadsorption is well tolerated by patients with AIDS-related Kaposi's sarcoma, and that this treatment has antitumor and immunomodulatory effects in these patients.

The number of total T-cells and the number of helper/inducer T-cells decreased in 27 of 31 patients with immunologic disorders treated with plasmapheresis and drug immunosuppression. The number of suppressor/cytotoxic T-cells increased in the majority of patients. The helper/inducer to suppressor/cytotoxic cell ratio, which was initially elevated in 26 of 31 patients, decreased significantly in all but 2 patients after therapy. Ten patients were already on drug immunosuppression at the time plasmapheresis was started, and all 10 showed increased helper/inducer to suppressor/cytotoxic cell ratio despite their drug therapy. The helper/inducer to suppressor/cytotoxic cell ratio decreased in all ten patients after plasma exchange. The number and the percentage of total T-cells and helper/inducer cells decreased from prepheresis levels while the number and the percentage of suppressor/cytotoxic cells increased. Plasmapheresis, in combination with drug immunosuppression, was effective in decreasing the elevated helper/inducer to suppressor/cytotoxic cell ratio in disorders of the immune system. In contrast, patients on immunosuppressive drug therapy alone had persistently high immunoregulatory ratio.

Because reduction of renal mass (nephrectomy) can promote the development of focal glomerulosclerosis in animals, we asked whether patients with unilateral renal agenesis might have similar lesions in the solitary kidney. We describe here the clinical course and pathologic findings of eight patients who developed focal and segmental glomerulosclerosis (FGS) in their solitary kidneys. A review of 586 surgical pathology renal specimens (452 biopsies and 134 nephrectomies) revealed 29 (4.9 per cent) cases of FGS; five also had unilateral renal agenesis (p = 2.1 x 10(-7)). In 9200 autopsies, seven cases of unilateral renal agenesis were found; two (29 per cent) died of chronic renal failure with FGS lesions, and five did not have FGS. The eighth patient was identified because he was the father of a patient in this series. At the time of diagnosis the median age of the patients with unilateral renal agenesis and FGS was 25 years; seven of eight were male. All had proteinuria; four had more than 3 gm. per 25 hours (range, 1.2 to 9.0 gm. per 24 hours). Six developed chronic renal failure, and four died of their renal disease. Two of the patients were related (father and son). One patient had clinical and morphologic evidence of reflux nephropathy. The glomerular lesions were characterized by focal and segmental scarring and adhesions in glomeruli, IgM and C3 deposition by immunofluorescence, and foot process loss and capillary loop collapse by electron microscopy. Our series, although small, indicates that patients with unilateral renal agenesis are significantly more likely to develop FGS than patients with two kidneys. In contrast, FGS did not develop after adult nephrectomy in 10 patients who died 8 to 46 years after adult unilateral nephrectomy. The reason for this association was not established; however, these findings are in accord with experimental studies in which subtotal nephrectomy in young animals promotes FGS. In that setting and in these patients, glomerular damage may result from glomerular overload.

Four patients with chronic, progressive demyelinating peripheral polyneuropathy were found to have paraproteinemia. Two of the patients had multiple myeloma [both immunoglobulin (Ig)G lambda]. The other two had benign gammopathies: one of IgG kappa type and the other one with marked polyclonal elevation of IgM. Immunofluorescence studies revealed deposits of the abnormal serum immunoglobulin along the myelin sheaths in two of the patients in whom sural nerve biopsies were performed. All four patients were treated with plasmapheresis in combination with immunosuppressive drugs. Favorable responses to the therapy was observed in all four patients, but the degree of response varied from patient to patient. Two patients who presented clinical and electromyographic findings consistent with polymyositis were found to have serum IgG kappa M components. Immunofluorescence studies performed on muscle biopsy material from both patients revealed deposits of the abnormal serum paraprotein along the sarcolemmal basement membrane. A treatment course of plasmapheresis and immunosuppressive drugs resulted in a sustained increase of muscle strength in both patients.

Nine homosexual patients with immune thrombocytopenia were treated with autologous plasma that had been perfused over silica-immobilized Staphylococcus aureus protein A (SpA). Pretreatment platelet counts ranged from 10,000 to 98,000 cells/mm3 (mean: 54,000 cells/mm3). Six patients responded to therapy. Platelets increased by a mean of 95,000 cells/mm3 (p less than 0.007) and reached normal levels (greater than 150,000 cells/mm3) in four patients. Increased platelet counts are presently sustained in these four individuals after 5 months of follow-up. Increases in platelet counts significantly correlated with decreases in platelet-associated IgG (PAIgG), platelet-directed IgG (PDIgG), and immune complexes (CIC). PAIgG and PDIgG declined by a mean of 67% (p less than 0.003) and 58% (p less than 0.007), respectively. CIC decreased by a mean of 37% (p = 0.02). Complement was concomitantly activated in all four examined patients. C3a and C5a increased 23-fold and 2.6-fold, respectively, while total hemolytic complement decreased by 50%. Activated complement components and removal of CIC and IgG thus may contribute to the platelet-enhancing activity of SpA immunoadsorption therapy.

The role of therapeutic apheresis was assessed in a number of clinical syndromes associated with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC). Four groups of patients were studied: AIDS with opportunistic infections, AIDS with Kaposi's sarcoma, AIDS/ARC patients with peripheral neuropathy and a patient with AIDS-related immune thrombocytopenia. Intensive plasmapheresis was shown to have no significant effects on the disease course of patients with full-blown AIDS. However, intensive plasma exchange restored normal neurologic function in the majority of patients with AIDS/ARC-related peripheral neuropathy. Selective immunoadsorption by means of protein A columns led to a sustained normalization of platelet counts in a patient with severe immune thrombocytopenia. A phase I study of AIDS-related Kaposi's sarcoma demonstrated that protein A immunoadsorption was tolerated well and was accompanied by partial responses. Patients being plasmapheresed for conditions other than AIDS were not found to be at any greater risk for acquiring AIDS-related viruses. Finally, health care professionals performing apheresis procedures on AIDS patients were not shown to be at increased risk of contracting AIDS-related viruses provided reasonable blood precautions were exercised.

In 35 homosexual men with isolated thrombocytopenia at initial presentation, who were evaluated and treated between 1982 and 1984, hematologic studies showed immune destruction. In contrast to findings in other autoimmune conditions, T-lymphocyte subsets in these patients were reversed, with a mean helper to suppressor ratio of 0.4 and with an absolute depletion of helper cells to 390/mm3. An enzyme-linked immunosorbent assay detected antibodies to human T-lymphotropic virus type III in 21 of 25 patients tested; Western blot analysis confirmed seropositivity in the other 4 patients, who had borderline findings. Although 19 of 24 patients treated with steroids responded, only 2 achieved sustained normal platelet counts. Ten of fifteen patients who had splenectomy achieved remissions. Three patients treated with steroids or splenectomy developed diagnoses compatible with the acquired immunodeficiency syndrome 16 to 34 months after their initial presentation with thrombocytopenia. These findings indicate that immune thrombocytopenia is part of the clinical spectrum of the acquired immunodeficiency syndrome.

Plasma of a homosexual man with Kaposi's sarcoma and acquired immunodeficiency was perfused over a protein A column using a continuous-flow plasma-cell separator. Three liters of plasma was perfused during each procedure and returned to the patient at a plasma flow rate of 10-20 ml/min. Three treatments were performed over a 1-week period. Transient removal of IgG, immune complexes, antilymphocyte antibodies, and serum blocking factors to mitogenic lymphocyte stimulation was observed during each treatment. Although no striking regression occurred, microscopic examination of sarcomatous lesions revealed decrease of tumor cell density and collagen proliferation within the tumor. Immunohistochemical deposition of C3 was observed in the tumor lesions after treatment. Side effects from the treatment included a mild drop of systolic blood pressure, sinus tachycardia, and a decrease in platelet count.