Biomedical subjects

G Hale

Publications and source records attributed to G Hale.

At least 55 records · Page 3Linked to original sources

PubMed2000

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity.

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.

Adult↗

PubMed2000

Local bioactive tumour necrosis factor (TNF) in corneal allotransplantation.

The aim of this study was to examine the kinetic profile of bioactive TNF levels in aqueous humour of rabbit eyes undergoing corneal allograft rejection and to investigate the effect of locally blocking TNF activity after corneal transplantation. In a rabbit corneal transplantation, endothelial allograft rejection was identified and correlated with increase in central graft thickness. Samples of aqueous humour obtained on alternate days following transplantation were tested for TNF mRNA and bioactive TNF protein. To investigate the effect of locally blocking TNF activity in allograft recipients, the fusion protein TNFR-Ig was administered by injections into the anterior chamber after transplantation. Pulsatile increases in levels of this cytokine were found in 14 of 15 allograft recipients. Peaks of TNF bioactivity preceded by varying intervals the observed onset of rejection in allograft recipients. TNF levels were not elevated in aqueous humour from corneal autograft recipient controls or in serum of allografted animals. mRNA levels were elevated before onset of and during clinically observed allograft rejection. In three of seven animals receiving TNFR-Ig injections on alternate days from day 8 to day 16 post-transplant, clear prolongation of corneal allograft survival was demonstrated. Bioactive TNF is present in aqueous humour following rabbit corneal allotransplantation. Rather than correlating directly with endothelial rejection onset, pulsatile peak levels of TNF precede and follow the observed onset of endothelial rejection. Blockade of TNF activity prolongs corneal allograft survival in some animals, indicating that this cytokine may be a suitable target in local therapy of corneal allograft rejection.

Animals↗

PubMed2000

Impact on T-cell depletion and CD34+ cell recovery using humanised CD52 monoclonal antibody (CAMPATH-1H) in BM and PSBC collections; comparison with CAMPATH-1M and CAMPATH-1G.

BACKGROUND: Ex vivo T-cell depletion of allogeneic BM (BM) grafts can effectively reduce graft versus host disease (GvHD) and may also apply to transplantation of allogeneic peripheral blood stem cell (PBSC) transplants. METHODS: Here we have evaluated T-cell depletion and progenitor cell recovery by antibody-mediated cells lysis using three CD52 monoclonal antibodies (MAbs) at different concentrations and cell densities. RESULTS: CAMPATH-1M was superior to CAMPATH-1H for T-cell depletion of BM samples. Treatment with CAMPATH-1M resulted in up to 2.55 log depletion of CD3+ cells, with recoveries of >or=45% CD34+ cells, >or=67% CFU-GM and >or=65% BFU-E. CAMPATH-1H treatment resulted in up to 1.64 log depletion of CD3+ cells and similar recoveries of CD34+ cells, CFU-GM and BFU-E as seen with CAMPATH-1M. Depletion of CD19+ cells was similar to that observed for CD3+ cells while natural killer (NK) cells were relatively spared compared with the T and B cell populations. Log depletions of T cells from PBSC, as determined by immunofluorescence studies and limiting dilution analyses, were similar using CAMPATH-1M, -1H, and -1G. There were also no differences in the depletion of CD19+ cells or NK cells using the three MAbs. Similar results were obtained for recoveries of CD34+ cells, CFU-GM and BFU-E using all three MAbs, although the recovery of CD34+ cells using the highest concentration of MAbs was significantly greater in CAMPATH-1H treated samples. Increasing the number of PBSC treated with CAMPATH-1H and -1M had no effect on the log depletion of T, B or NK cells and there were no major differences in the log depletions achieved with CAMPATH-1H or -1M. Likewise, the higher PBSC density had no effect on the recoveries of CD34+ cells or committed progenitors and once again CAMPATH-1H gave similar recoveries to those obtained using CAMPATH-1M. DISCUSSION: Although CAMPATH-1M resulted in greater ex vivo T-cell depletion of BM than CAMPATH-1H, in all other respects, the humanised CAMPATH-1H was just as effective as CAMPATH-1M and -1G.

Alemtuzumab↗

PubMed2000

The CD45 tyrosine phosphatase regulates Campath-1H (CD52)-induced TCR-dependent signal transduction in human T cells.

Campath-1H, a humanized mAb undergoing clinical trials for treatment of leukemia, transplantation and autoimmune diseases, produces substantial lymphocyte depletion in vivo. The antibody binds to CD52, a highly glycosylated molecule attached to the membrane by a glycosylphosphatidylinositol anchor. Cross-linked Campath-1H is known to activate T cells in vitro. We have investigated the molecular basis for these effects by comparing the protein tyrosine phosphorylation signals induced by Campath-1H and the CD3 mAb OKT3 in primary T cells, and in CD45(+)TCR(+), CD45(-)TCR(+) and CD45(+)TCR(-) Jurkat subclones transfected with CD52. Our results show that Campath-1H triggers similar tyrosine phosphorylation events as OKT3 in both primary T cells and in the CD45(+)TCR(+) Jurkat sub-clone, albeit at quantitatively lower levels. However, no phospholipase C gamma 1 activation nor calcium signals were detected in response to CD52 ligation. The CD52-mediated induction of protein tyrosine phosphorylation was absolutely dependent upon the expression of both the TCR and the CD45 phosphotyrosine phosphatase at the cell surface. Cross-linking of Campath-1H was essential for signal transduction in all cells investigated. Fluorescence resonance energy transfer was used to demonstrate CD52 homo-association at the cell surface in Jurkat T cells in a TCR- and CD45-independent manner, and CD52-TCR association in CD45(+)TCR(+) cells. We propose a model to explain the activating effects of Campath-1H in which CD52 mAb cross-linking causes the trapping of TCR polypeptides within molecular complexes at the cell surface, thereby inducing signals via the TCR by a process which depends on the CD45-mediated regulation of the p56(lck) and p59(fyn) tyrosine kinases.

Alemtuzumab↗

PubMed2000

Campath-1H therapy in refractory ocular inflammatory disease.

BACKGROUND: Standard therapy for severe, immune mediated, ocular inflammation has significant side effects, and may fail to control the disease. T cell directed monoclonal antibody (mAb) therapy can provide long term remission of inflammatory disease in experimental models. The Campath-1H mAb was administered to patients with severe, refractory, ocular inflammation. METHODS: 10 patients with severe, refractory, non-infectious ocular inflammatory disease were treated with Campath-1H mAb. This is a fully humanised mAb which recognises the pan-lymphocyte antigen CD52. RESULTS AND DISCUSSION: Following Campath-1H therapy, all 10 patients showed an initial resolution of their ocular symptoms and signs. Long lasting remissions were achieved in eight patients, in whom baseline immunosuppression could subsequently be reduced to minimal levels. The possible mechanisms of action of Campath-1H therapy are discussed.

Adult↗

PubMed2000

Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients.

The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.

Adult↗

PubMed1999

Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection.

BACKGROUND: The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts. METHODS: We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes. RESULTS: None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection. CONCLUSIONS: These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.

Amino Acid Substitution↗

PubMed1999

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.

Adult↗

PubMed1999

Anti-globulin responses to rat and humanized CAMPATH-1 monoclonal antibody used to treat transplant rejection.

BACKGROUND: Antiglobulin responses are a significant limitation to the repeated use of murine monoclonal antibodies for treatment of transplant rejection. It is hoped that these might be largely overcome by using antibodies genetically engineered to resemble human antibodies. METHODS: We have compared the responses in patients treated with the CD52 monoclonal antibodies CAMPATH-1G (rat IgG2b) or its humanized derivative, CAMPATH-1H (human immunoglobulin G1). RESULTS: A majority of patients (15 of 17) made responses to the rat antibody, but there were no detectable responses to the humanized antibody (0 of 12). CONCLUSIONS: Although anti-idiotype responses are theoretically possible against humanized therapeutic antibodies and are especially likely to be provoked by cell-binding antibodies, these data show that humanization offers a significant reduction in immunogenicity, potentially allowing repeat courses of treatment.

Alemtuzumab↗

PubMed1999

Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis.

BACKGROUND: Multiple sclerosis results from T-cell-dependent inflammatory demyelination of the central nervous system. Our objective was long-term suppression of inflammation with short-term monoclonal antibody treatment. METHODS: We depleted 95% of circulating lymphocytes in 27 patients with multiple sclerosis by means of a 5-day pulse of the humanised anti-CD52 monoclonal antibody, Campath-1H. Clinical and haematological consequences of T-cell depletion, and in-vitro responses of patients' peripheral-blood mononuclear cells were analysed serially for 18 months after treatment. FINDINGS: Radiological and clinical markers of disease activity were significantly decreased for at least 18 months after treatment. However, a third of patients developed antibodies against the thyrotropin receptor and carbimazole-responsive autoimmune hyperthyroidism. The depleted peripheral lymphocyte pool was reconstituted with cells that had decreased mitogen-induced proliferation and interferon gamma secretion in vitro. INTERPRETATION: Campath-1H causes the immune response to change from the Th1 phenotype, suppressing multiple sclerosis disease activity, but permitting the generation of antibody-mediated thyroid autoimmunity.

Adult↗

PubMed1999

Male-specific modification of human CD52.

CD52 is an unusually short, bipolar glycopeptide bearing a highly charged N-linked carbohydrate moiety and a glycosylphosphatidylinositol membrane anchor. It is exclusively expressed on lymphocytes and in the male genital tract where it is shed into the seminal plasma and inserts into the sperm membrane. The sperm surface molecule has potential significance as a target for antibodies that inhibit sperm function and gamete interaction. Western blot analyses suggested cell type-specific modifications of the antigen. It was purified from seminal plasma and a detailed structural analysis performed. The majority of anchor structures in male genital tract CD52 showed 2-inositol palmitoylation, rendering molecules insensitive toward phospholipase C, and a sn-1-alkyl-2-lyso-glycerol structure in place of the diacylated anchor described by Treumann et al. (Treumann, A., Lifely, M. R., Schneider, P., and Ferguson, M. A. (1995) J. Biol. Chem. 270, 6088-6099). N-Glycans of the male genital tract product were based on bi-, tri-, and tetraantennary structures of highly charged (up to -7), terminally sialylated complex-type sugars. A substantial proportion carried varying numbers of lactosamine repeats of which nearly 30% were branched. Different from lymphocytes, 10-15% of all N-glycans of the male genital tract antigen also contained peripheral fucose. These data confirm that male genital tract CD52 is distinct from the lymphocyte form by both N-linked glycans and COOH-terminal attached lipid anchor.

Antigens, CD↗

PubMed1999

Children with acute lymphoblastic leukemia who receive T-cell-depleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome.

Disparity for HLA in unrelated donor bone marrow transplantation (BMT) increases the risk of graft rejection and graft-versus-host disease (GVHD) and may compromise transplant outcome. We have compared the outcome of matched and mismatched transplants from unrelated donors in 137 children with acute lymphoblastic leukemia (ALL). Their disease status was complete remission (CR)-1, 24 patients; CR-2, 88 patients; CR-3, 18 patients; CR-4, 2 patients; and relapse, 5 patients. CAMPATH monoclonal antibodies were used for T-cell depletion and cyclosporin A was given to 134 children together with short-course methotrexate in 43, mainly when there was HLA disparity. Fifty-two donor/recipient pairs were HLA-mismatched, 41 at HLA-A and -B and 11 at HLA-DR and -DQ loci. Overall graft failure was increased in recipients of marrow mismatched at either HLA-A, -B, -DR, or -DQ (15.7% v 4.8%; P =.057) mainly because there was a higher proportion of children with primary graft failure (11. 8% v 1.2%; P =.012). The presence of an HLA-C locus mismatch did not independently increase the likelihood of graft failure. There was no significant difference in the incidence of acute GVHD >/= grade 2 between the matched and mismatched groups (P =.849). For patients in CR-2, the risk of relapse post-BMT was significantly lower if leukemic relapse occurred off-treatment (P =.005). The Kaplan-Meier overall and leukemia-free survival (LFS) estimates for recipients of matched and mismatched BMT, respectively, at 36 months were 49% versus 42% (P =.380) and 45% versus 40% (P =.654). Although HLA mismatching results in an increased occurrence of primary graft failure with T-cell-depleted allografts, it allows more donors to be identified rapidly for children with ALL without compromising overall transplant outcome.

Adolescent↗

PubMed1999

1.9 A structure of the therapeutic antibody CAMPATH-1H fab in complex with a synthetic peptide antigen.

CAMPATH-1 antibodies have a long and successful history in the treatment of leukaemia, autoimmune disease and transplant rejection. The first antibody to undergo "humanisation", CAMPATH-1H, permits treatment with limited patient anti-globulin response. It recognises the CD52 antigen which is a small glycosylphosphatidylinositol(GPI)-anchored protein expressed on lymphocytes and mediates cell depletion. We present the 1.9 A structure of the CAMPATH-1H Fab complexed [corrected] with an analogue of the antigenic determinant of CD52. Analysis of the CAMPATH-1H binding site reveals that in contrast to most antibodies CDR L3 plays a dominant role in antigen binding. Furthermore CDR H3, which is essential for effective antigen recognition in most antibodies, participates in only two main-chain interactions in CAMPATH-1H. The CAMPATH-1H binding site is highly basic; ionic interaction with the enthanolamine phosphate of the CD52 GPI anchor has long been hypothesised to be important in antigen binding. The structure reveals a number of important specific ionic interactions, including Lys53H but not Lys52bH as had previously been suggested. Prolonged treatment with CAMPATH-1H can lead to patient anti-idiotype responses which may be exacerbated by the unusually high number of basic residues in the antibody. This suggests that a strategy where redundant basic residues are replaced with neutral counterparts may be effective in further reducing the immunogenicity of this versatile and widely used antibody.

Alemtuzumab↗

PubMed1999

Epstein-Barr virus (EBV) associated B-cell lymphoproliferative disease following HLA identical sibling marrow transplantation for aplastic anaemia in a patient with an EBV seronegative donor.

BACKGROUND: B-cell lymphoproliferative disorders (BLPD*) caused by Epstein-Barr virus (EBV) occurring after allogeneic bone marrow transplantation (BMT) are usually of donor origin. Treatment such as discontinuation of immunosuppression may be successful in some cases, but infusion of donor T cells results in successful eradication of EBV BLPD in most cases. METHODS AND RESULTS: We report a case of EBV positive aggressive BLPD after HLA matched sibling BMT for aplastic anaemia. The tumour completely regressed after withdrawal of cyclosporin and donor lymphocyte infusion. However, although the tumor was of donor origin, the donor serum was negative for antibodies to EBV antigens and no EBV-specific cytotoxicity was detected in donor peripheral blood mononuclear cells. The recipient was seropositive for EBV before BMT. CONCLUSIONS: We speculate that a 'second primary' EBV infection occurred involving donor cells in the recipient during BMT immunosuppression, with subsequent outgrowth of donor-derived BLPD. EBV infection may have been by an endogenous EBV isolate, from external sources, or from third party transfusions.

Adult↗

PubMed1999

Elimination of the immunogenicity of therapeutic antibodies.

The immunogenicity of therapeutic Abs limits their long-term use. The processes of complementarity-determining region grafting, resurfacing, and hyperchimerization diminish mAb immunogenicity by reducing the number of foreign residues. However, this does not prevent anti-idiotypic and anti-allotypic responses following repeated administration of cell-binding Abs. Classical studies have demonstrated that monomeric human IgG is profoundly tolerogenic in a number of species. If cell-binding Abs could be converted into monomeric non-cell-binding tolerogens, then it should be possible to pretolerize patients to the therapeutic cell-binding form. We demonstrate that non-cell-binding minimal mutants of the anti-CD52 Ab CAMPATH-1H lose immunogenicity and can tolerize to the "wild-type" Ab in CD52-expressing transgenic mice. This finding could have utility in the long-term administration of therapeutic proteins to humans.

Alemtuzumab↗

PubMed1999

Ex vivo depletion of T cells from bone marrow grafts with CAMPATH-1 in acute leukemia: graft-versus-host disease and graft-versus-leukemia effect.

BACKGROUND: Preventing graft-versus-host disease (GVHD) by depletion of T lymphocytes from the stem cell graft for transplantation remains controversial, mainly because of the perceived increase in disease recurrence. METHODS: We retrospectively analyzed the outcome of 50 consecutive individuals in remission of acute lymphoblastic leukemia (n=13; 8 in complete remission [CR]1) or acute myeloblastic leukemia (n=37; 33 in CR1), who had received marrow grafts from HLA-identical siblings. The conditioning regimen included six 2-Gy fractions of total body irradiation, succeeded by cyclophosphamide at 120 mg/kg (with mesna) followed by four fractions of 1.5 Gy to lymphoid areas. Bone marrow (n=38) or peripheral blood mobilized donor mononuclear cells (n=12) were exposed ex vivo to CAMPATH-1 (IgM and complement, or IgG; antiCD52) antibodies, without any further posttransplantation immunosuppression. RESULTS: Median patient age was 31 (range 14-51) years; 12 patients were 40 or older. Thirty-two patients were male. One patient died of pulmonary hemorrhage on day 10; another died on day 29 of interstitial pneumonitis. Except for one early death, all patients engrafted. Ten (21%) of the remaining 48 who were at risk, developed GVHD. In none was it greater than grade II. Eight patients developed serious viral infections. Four died of cytomegalovirus pneumonia, adenovirus hepatitis, and human immunodeficiency. Overall, 11 patients (22%) relapsed (4 of 33 acute myeloblastic leukemia in CR1) at a median of 235 (range 46-528) days. Mean posttransplantation follow-up was 1062 (median 560; range 10-4177) days. Thirty-three patients (66%) remained disease free at a mean of 1,118 (median 1439; range 159-4,177) days. For all patients, the performance status was between 82% and 100% (median 100). CONCLUSION: T-cell depletion with CAMPATH-1 effectively prevents GVHD, particularly the severe acute forms, without leading to excessive risk of relapse in acute leukemia.

Adolescent↗

PubMed1999

The relationship between pityriasis rubra pilaris and inflammatory arthritis: case report and response of the arthritis to anti-tumor necrosis factor immunotherapy.

Pityriasis rubra pilaris (PRP) refers to a group of erythematous, scaling dermatologic conditions that have been associated with seronegative arthritis. We report a case of polyarthritis in a young man with PRP in which magnetic resonance imaging suggested an entheseal-based pathology for the joint disease. The arthritis, but not the skin condition, demonstrated dramatic response to anti-tumor necrosis factor immunotherapy.

Adolescent↗

PubMed1999

Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

Adult↗