Serum immunoglobulin levels in relation to levels of specific antibodies in allogeneic and autologous bone marrow transplant recipients.

BACKGROUND: The aim of this study was to investigate the correlation of total levels of immunoglobulins to levels of specific antibodies after allogeneic and autologous bone marrow transplantation. Autologous transplant patients had normal levels of IgA and IgG antibodies already at 6 months after transplantation. In allogeneic transplanted patients without chronic graft versus host disease the immunological recovery was slower. The IgA and IgG levels were at the limit for deficiency at 6 months after transplantation. In allogeneic transplant patients with chronic chronic graft versus host disease the immunological recovery was delayed further. The total IgG levels were low at 12 months after transplantation and the IgG subclass pattern did not normalize until 24 months after transplantation. IgA levels remained low at 24 months after transplantation in all allogeneic transplanted patients with chronic chronic graft versus host disease. Protective levels of specific antibodies against tetanus and pneumococci decreased during the first year after transplantation regardless of the total immunoglobulin levels, regardless of the donors immunity. Pneumococcal antibodies decreased only in allogeneic transplanted patients, although autologous transplant patients retained pretransplant immunity against pneumococci. There was no difference in levels of specific antibodies between patients with and without chronic chronic graft versus host disease at 12 months after transplantation. There was no correlation between total immunoglobulin levels to levels of specific antibodies against tetanus and pneumococci after transplantation in our study. Taken together, normalized immunoglobulin levels do not predict normalization of levels of specific antibodies against tetanus and pneumococci after transplantation.

Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the serological response at influenza vaccination was studied in 117 patients who had undergone stem cell transplantation (SCT). The vaccine response was evaluated as significant increases in levels of influenza hemagglutination-inhibition (HAI) antibodies and of IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). There was no difference in antibody response to either influenza A or B in 64 patients who received GM-CSF at vaccination, compared with the 53 who did not. In the subgroup of allogeneic SCT patients, HAI showed that the response rate to the influenza B vaccine was significantly higher in the treatment group (P<.05). ELISA showed that autologous SCT patients with breast cancer who received GM-CSF had a better response to influenza A (P<.05) and B (P<.01). At early vaccination, 4-12 months after stem cell transplantation, these responses were more pronounced. GM-CSF appears to improve the response to influenza vaccination in some groups of SCT patients, but only to a limited extent.

Tetanus immunity in autologous bone marrow and blood stem cell transplant recipients.

The aims of this study were to assess long-term immunity and reimmunization responses against tetanus toxoid in recipients of autologous stem cell grafts and to compare immune status in patients who underwent ABMT or autologous blood stem cell transplantation (APBSCT). Ninety patients were included in the study; 52 had received ABMT and 38 APBSCT. Thirty of 52 ABMT patients (58%) and 25 of 38 APBSCT patients (66%) had protective antibody levels against tetanus before transplantation (P = NS). The rate of seropositivity had decreased at 1 year after transplantation; 15 of 52 (29%) ABMT patients and 18 of 38 (47%) APBSCT patients (P = NS) were still positive after 1 year. There were no cases of spontaneous recovery in seronegative patients. Most patients were reimmunized with three doses of tetanus toxoid given at 12, 13, 14 and or 18 months after transplantation. All immunized patients had protective immunity against tetanus at 1 year after vaccination. These results suggest that humoral immunity is defective both after ABMT and after APBSCT and in both cases the loss of immunity seems to be similar. Reimmunization of patients who have undergone ABMT or APBSCT is necessary to obtain protective immunity against tetanus.

Long-term immunity to measles, mumps, and rubella after allogeneic bone marrow transplantation.

A total of 124 patients who had survived at least 2 years after allogeneic bone marrow transplantation (BMT) were studied. Serum was collected at least once yearly. IgG antibodies were determined by enzyme-linked immunosorbent assay for measles and mumps. Rubella antibodies were analyzed by radial hemolysis. Antibody levels were interpreted as representing immunity, seronegativity, or seropositivity, but with uncertain immunity. The median follow-up of the patients was 6.5 years (range, 2 to 13.5 years). The calculated probabilities of being immune to measles at 3, 5, and 7 years from BMT were 47%, 27%, and 20%, respectively. The corresponding probabilities for mumps were 37%, 12%, and 6%, respectively; and for rubella, 47%, 33%, and 28%, respectively. The probabilities for being seronegative for measles, mumps, and rubella at 5 years after BMT were 60%, 73%, and 52%, respectively. When compared with those patients who had experienced previous natural measles disease (P < .05), the only factor that was important for immunity to measles after BMT was whether the patient had been immunized before BMT. There was no influence of donor seropositivity on the probability of becoming seronegative to mumps during follow-up. We conclude that most allogeneic patients will become seronegative to measles, mumps, and rubella during follow-up. Therefore, long-term B-cell memory function is not maintained, regardless of the immune status of the donor.

Immunity to poliovirus and immunization with inactivated poliovirus vaccine after autologous bone marrow transplantation.

Titers of antibody to poliovirus in 102 patients were determined with a sensitive neutralization assay before and 1 year after autologous bone marrow transplantation. At 1 year 14 patients (14%) had lost antibodies to poliovirus type 1 (P < .001), 10 (10%) to poliovirus type 2 (P < .05), and 13 (13%) to poliovirus type 3 (P < .01). Twenty-two patients had lost antibodies to at least one type of poliovirus. Follow-up of unimmunized patients 2 years (n = 40) and 3 years (n = 23) after transplantation documented a continuous decrease in antibody titer; by 3 years after transplantation, another 6 patients had become seronegative. When one dose of inactivated trivalent poliovirus vaccine was administered 1 year after transplantation, 2 (25%) of 8 patients seronegative for poliovirus type 1 had an increase of at least fourfold in antibody titer; after three doses, 10 (83%) of 12 patients exhibited such an increase (P < .05). The corresponding figures were 5 (71%) of 7 and 13 (100%) of 13 for poliovirus type 2 (difference not significantly) and 2 (22%) of 9 and 14 (88%) of 16 for poliovirus type 3 (P < .01). These results indicate that at least 30% of patients undergoing autologous bone marrow transplantation including those seronegative for poliovirus before transplantation will benefit from reimmunization with three doses of inactivated trivalent poliovirus vaccine 1 year after transplantation.

Pneumococcal immunity and response to immunization with pneumococcal vaccine in bone marrow transplant patients: the influence of graft versus host reaction.

The aim of this study was to evaluate levels and subclass distribution of pneumococcal antibodies in 40 bone marrow transplant (BMT) and 42 autologous bone marrow transplant (ABMT) recipients during the first year after transplant, and response to vaccination with a polyvalent pneumococcal vaccine. Before transplantation, 35/40 recipients of allogeneic grafts, all 42 autologous BMT recipients and 38/39 donors had adult levels of anti-pneumococcal antibodies of the IgG2 subclass. During the first year after transplantation, antibody levels decreased in 29 BMT patients while 11 retained their pretransplant antibody levels. No change was noted among ABMT patients. In the 8 BMT patients who had chronic graft versus host disease (GVHD), none showed normal levels of anti-pneumococcal antibodies 1 year after BMT as compared to 11/32 without chronic GVHD. Three different response patterns were seen after vaccination of 29 BMT patients who lost immunity with a polyvalent pneumococcal vaccine. Ten patients responded with an increase in IgG2 antibodies, 8 responded with an increase in IgG1 and 11 patients did not respond at all. In the 8 patients with chronic GVHD, none responded with an increase in IgG2 antibodies and 6/8 did not respond at all. The results of this study suggest that chronic GVHD is the main factor contributing to loss of immunity to pneumococci and lack of responsiveness to vaccination with pneumococcal polysaccharides after BMT. Furthermore, the difference in capability, between BMT and ABMT recipients, of retaining anti-pneumococcal activity may explain the clinical experience of severe pneumococcal infections in these patients.

Transfer by BMT of IgG2 deficiency involving an immunoglobulin heavy chain constant region deletion and a silent IgG2 gene.

A patient suffering from ALL who underwent allogeneic BMT developed complete IgG2 deficiency after BMT. When the donor Ig serum levels were examined, it was found that he also lacked detectable levels of IgG2. The IGHC genes were investigated and a heterozygous 50-70 kb deletion encompassing the genes coding for IgG2 (G2) and IgG4 (G4) (del G2-G4) was found in the white blood cells. The patient had IgG2 levels in the low normal range before BMT. When the patient's fibroblasts were examined to determine his original genotype, they were found to carry the same deletion haplotype, but in combination with a different G2 allele than that present in the transplanted BM cells. The combination of Ig heavy chain constant region gene alleles found in the transplant has also been inherited by a third brother also lacking IgG2. The hemizygous G2 allele present in the donated BM cells was thus 'silent' and the complete IgG2 deficiency had been transferred by the BMT.

Cytomegalovirus viraemia and specific T-helper cell responses as predictors of disease after allogeneic marrow transplantation.

Risk factors for cytomegalovirus viraemia and disease, the relation between viraemia and disease, effect of antiviral treatment, and T-helper cell response to cytomegalovirus antigen were analysed retrospectively among 279 patients who underwent bone marrow transplantation at Huddinge Hospital. Ninety-one of 279 (32.6%) patients developed viraemia. Donor and recipient pre-transplant serologic status and degree of acute graft-versus-host disease were independent risk factors for viraemia. Forty-nine patients (17.6%) developed cytomegalovirus disease and 44 of these patients had viraemia. Seventeen patients (6%) developed cytomegalovirus pneumonia and 14 of these patients had preceding viraemia. Among patients with viraemia, acute graft-versus-host disease and total body irradiation were risk factors for pneumonia. Antiviral treatment initiated within 7 d of development of viraemia was associated with lower risk for development of pneumonia (P < 0.05). Sixty-seven patients with viraemia were repeatedly tested by lymphocyte stimulation with cytomegalovirus antigen. No patient who developed cytomegalovirus pneumonia had measurable specific helper T-cell response at the time of viraemia detection compared to 42% of patients with other concurrent or subsequent cytomegalovirus disease, and 75% of patients without subsequent disease. We conclude that viraemia is a major risk factor for development of cytomegalovirus disease. Furthermore, early antiviral treatment based on detection of viraemia can be effective in preventing cytomegalovirus disease. The length of antiviral treatment might be decided through measurements of the helper T-cell response to cytomegalovirus antigen.