Combined B-Cell and T-Cell Disorders Treatment & Management
- Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Emmanuel C Besa, MD more...
Patients with combined immunodeficiencies, such as SCID, XHM, Good syndrome, and WAS, may benefit from intravenous immunoglobulin (IVIG) replacement therapy. Appropriate supportive care, such as early identification of opportunistic infections or nutritional support, are necessary.
- In WAS, other than prophylactic antibiotics and IVIG, splenectomy for thrombocytopenia and platelet transfusion in acute life-threatening bleeding can be used.
- NOTE: Do not immunize these patients with live attenuated vaccines.
- Focus efforts on the treatment of infections, allergic reactions, and autoimmune and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering Streptococcus pneumoniae and Haemophilus influenzae is indicated. Prophylactic antibiotic therapy has been recommended for patients with frequent infections. A course of metronidazole may result in dramatic improvement of the patients' diarrhea and, to a certain extent, of malabsorption syndrome. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.
- Patients with ADA deficiency may benefit from substitution with pegademase bovine ADA. The maximum effect on immunologic function does not occur for several months. (see the package insert for details.)
- Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. This treatment strategy is highly successful when a human leukocyte antigen (HLA)-matched sibling donor is available; if such a donor is not available, however, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunologic complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative (see below). Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) may be helpful for patients with SCID. Survival rates in these previously fatal conditions are around 90% in some case series.
- The discovery of the HLA system in 1968 led to successful bone marrow transplantations. Patients with immunodeficiency syndromes were the first to benefit from this novel therapy.
- Allogeneic bone marrow transplantation has become the standard of care for certain patients with SCIDs (eg, XSCID, ADA deficiency). Patients with other immunodeficiency syndromes may benefit from bone marrow transplantation or HSCT, including those with WAS or XHM.
- There are many groups that are exploring the potential benefits of HSCT based on alternative donors. There are several advantages of umbilical cord blood stem cell transplantation (UCBSCT), which include ready availability of the unit, a lower risk of transmitting viral diseases, no risk to the donor, and a lower risk of GVHD even in the absence of a perfect HLA match.
- Another possibility for patients without a suitable sibling donor is a matched unrelated donor (MUD) HSCT. But in clinical practice, this therapy is limited due to high rates of GVHD and transplant-related mortality.
- To facilitate the identification of a suitable MUD, there have been recent advances, including the following: (1) the continuous growth of volunteer donors worldwide; (2) high-resolution molecular techniques for HLA typing, which permits a better selection of donors; and (3) advances in critical care that have resulted in a significant decrease in MUD-HSCT transplant related mortality and an increase in the survival of SCID infants who are severely infected at the time of diagnosis.
- Early diagnosis before the development of permanent lung and liver damage and referral to a specialized center for bone marrow transplantation/HSCT are essential for therapeutic success.
- Bertrand et al reported on a European experience with 178 patients in 18 centers who were treated with HLA, nonidentical, T-cell–depleted bone marrow transplantation. With a median follow-up of 57 months, disease-free survival was shown to be significantly better for patients with B-positive SCID (60%) than for patients with B-negative SCID (35%).
- Buckley et al found that the survival rate was not affected by the genetic type, but it was affected by race (ie, more white patients than black or Hispanic patients survived [P < 0.001]) and sex (all girls survived [P = 0.047]).
- Another report noted the inefficacy of bone marrow transplantation in correcting Job syndrome.
- Despite the success that has been seen in some SCID patients treated with bone marrow transplantation, in some cases, failure to restore B-cell function or failure or rejection of the graft over time occurrence. A novel alternative strategy to circumvent graft failure/rejection is the use of gene transfer into autologous stem cells using retroviruses.
- Gene therapy is a viable therapeutic option; advances in biotechnology have enabled the performance of this highly complex treatment for several immunodeficiency syndromes.
- Cavazzana-Calvo et al published reports of the successful results of gene therapy for SCID-X1 disease in 2 children, opening new horizons for the future of these patients. This therapy resulted in complete immune reconstitution of the lymphoid system, with T-, B-, and NK-cell counts comparable to age-matched controls. An update on these 2 patients by the same authors and a report on 3 others confirmed the previous results.
- Patients with ADA deficiency were the first to be enrolled in gene therapy trials. Until recently, no successful sustained expression of ADA occurred in treated patients. A trial conducted by Kohn et al is under way.
- Novel forms of gene therapy are being tested in clinical studies.[5, 20] One approach known as gene-modified autologous HSCT has shown some promising results; this therapy has the potential to circumvent the significant limitations of allogeneic bone marrow transplantation and gene therapy by using postthymic differentiated cells.
- RNA viruses are the most commonly used vectors to introduce genetic information into hematopoietic stem cells and/or progenitor cells. There have been reports of spontaneous, partial corrections of the phenotype of severe T-cell immunodeficiencies (eg, ADA deficiency, SCID-X1, WAS, RAG1 deficiency, CD3 deficiency) within the past decade. It has been demonstrated that several T-cell precursors which carry a wild-type sequence of the disease-causing gene or mutation with less harmful effects can mature into functional mature T cells that provide adequate immunity. The selective advantage conferred by the expression of either gamma C or ADA in lymphocyte progenitors was confirmed in 3 gene therapy clinical trials.
- It is striking to note that gene therapy for ADA deficiency was only successful in patients who did not concomitantly receive polyethylene glycol–ADA (PEG-ADA) enzymatic substitution.
Consultations should be obtained with specialists from the following specialties:
- Bone marrow transplantation
- Infectious diseases
In view of the presence of chronic diarrhea, patients often require enteral or parenteral supplementation.
Physical activity should be encouraged. Patients may need isolation to decrease the risk of common viral and bacterial infections, such as avoiding crowded places. Strict hygienic practices are important.
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|Pathophysiology||Cells Affected||Inheritance||Genes Involved|
|Premature cell death||T, B, NK||AR||ADA|
|Defective cytokine–dependent survival signaling||T, NK||AR|
γ c type-XL
|JAK3, IL7RA (T cells only), γ c|
|Defective V(D)J rearrangement||T, B||AR||RAG1, RAG2, Artemis|
|Defective pre-TCR and TCR signaling||T||AR||CD3 δ, CD3 ζ, CD3 ε,|
|AR = autosomal recessive; JAK3 =Janus tyrosine kinase 3; RAG1, RAG2 = recombinase activating gene 1 and 2, respectively; TCR = T-cell receptor; XL = X-linked; V(D)J = variable diversity joining.|